BridgeBio Pharma, Inc. (BBIO) Earnings Call Transcript

[Presentation] Thank you all for taking the time to join us today. For those of you that saw that video, there are several important pieces of context in there. We're going to be talking about the R&D that animates us here at BridgeBio. But it's really only important inasmuch as it helps us to serve patients with genetic disease. Elliott, who we've spoken about before, suffers from MOCD Type A. And I'm grateful to say that we have filed and had accepted for priority review by the FDA, or NDA, for that disease. And my hope is, with your support and through repeated application of our R&D engine over the course of the coming years, that Elliott is the first of hundreds of thousands of potentially millions of patients that we can help together. The second piece of context actually relates to that number, hundreds of thousands or millions. From the get-go of BridgeBio, our ambition has been one of scale and growth. It is not to say that we just want to progress the last couple of products in our pipeline to the marketplace. But rather, we see this as being day one in the area of genetic medicine, and we want to build a sustainable engine that continue to come up with new ideas as well as to progress our existing ideas towards the marketplace to fully take advantage of the innovation that is here and now today. So I'm going to talk about that as we move through the slides. But I'd like to start with just a brief reminder as to who we are. We're BridgeBio, we're a clinical stage biopharmaceutical company focused solely in the area of genetic medicine. By that, we see really there being 2 main areas. #1 is the area of Mendelian or monogenic disease, of which there are 78,000 separate diseases. And secondly, we see there being the area of somatic cancers with clear genetic drivers. The goal for us really is to be an engine that sits on top of all of the great innovation that's occurring in academia, mostly. And what that innovation is doing is allowing us to understand mechanism of disease to go from genetic aberrance to protein aberrance, to molecular path physiology to symptomatology and often, it will surface hypothesis as to how we might target that now well-described disease at its source. And that's where we get involved. We partner with these great academics to try to take those early hypotheses and translate them into medicines that matter as quickly as possible. So what does an engine look like with respect to that opportunity? There are several different ways you might resolve it. The way that we tend to resolve it and talk about it is by way of products. And products are important. Ultimately, they are the things that make a difference in patient lives, and they are the things that make a difference for investors. And we're going to talk about products at length today. We've got [ 470 ] products that will have catalysts over the next 12 to 24 months, in big $750 million or more marketplaces. And we'll talk about our targeted oncology portfolio as well, which hopefully will give rise to products over the course of the next year or 2 that we can interrogate in the clinic. So that's important. But what I wanted to spend my 20 minutes with you today speaking about is actually the platform or product engine that gives rise to those products. And to start, the organizing principles and strategy that gives rise to the product engine. And the reason I want to do that is my hope is after hearing that. And if you like what we've done over the course of the last 5 years in terms of those products we've created, that you want to partner with us, not only on our existing product pipeline, but also on the new ideas to come as we try to scale into this opportunity within genetic medicine that's bounded in here and now. All right. So let's start with strategy. One of the things that we always try to do when we start thinking about a strategy is to determine what the opportunity space is. And we've said this several times, we believe this is day 1 in the era of genetic medicine. You can determine that through a couple of different lenses. First is obviously the amount of innovation that's occurring in this space looking forward. If you look at disease-causing genes that are being identified every year, we're up to the hundreds now. The number has quantitatively doubled over the last couple of decades. And the number of common disease, GWAS, associations is also dramatically increasing. This is all due to the trends that we could spend an hour talking about decreasing costs and increasing quality of exome and genome sequencing and availability of longitudinal databases that allow us to understand the mutation and its importance within a set of symptomatology in a dramatically better way than we were, let's say, even 5 years ago. So I don't think I need to belabor the point. We really are in the early innings of what is a revolution in understanding the rare variant hypothesis and monogenic disease. Another way to dementalize the opportunity is to think about it from the patient backwards. And here, we think about 3 different cuts of the data. Number 1 is the total number of people affected. You can see from the blue shaded bars here that tens of millions of Americans alone are affected by these genetic diseases or somatic cancers with clear genetic drivers, although many of these diseases are individually quite rare and in aggregate, they're quite common. The second way to think about it is the impact of these diseases when one does unfortunately acquire condition. And this is the second or third largest driver of morbidity and mortality in childhood. These are severe diseases. And the impact is quite high. A third way, one might resolve how important this sector is and what the unmet need is, is the number of pharmacologic treatments that are available. You can see only 5% within the context of monogenic disease alone. Maybe on a risk-adjusted basis, another 10% to 15% over the course of the next 5 years. So there's plenty of these diseases to go after, plenty of opportunity for us to help patients. So how do we create this engine, this company that can scale into this opportunity and work as quickly as possible to create medicines that matter for these patients? We started really by going back in history to look at strategy. And we started with this book called strategy history. It's really a long book. It's a couple of thousand pages. I'll save you the reading. It's by Laurence Freeman. It's a beautiful book because it goes through the history of military strategy as well as corporate strategy. But one of the important lessons that comes out of it is that oftentimes, the best strategies have 3 simple elements: number one, they establish the correct playing field. Number two, they establish simple tenants that everyone can abide by. And number three, they allow their entities to stay adaptive. Now this might sound totally generic, but it's not. It actually stands in contrast to a lot of what we hear in the biopharmaceutical sector, which is, I am going to own this therapeutic area for the next 10 years or I am going to own the specific modality for the next decade to come. Rather, what we try to do is to learn from these principles and say, we're going to place ourselves in the right play field, that's GE genetic disease. You look backwards in time, probability of technical success is very high. Our ability, as we just mentioned, to be alongside of where innovation is going, is there in genetic disease. I don't know which genetic disease when we would have started would be the right one, but we're going to put ourselves on that playing field. Number two, we're going to opportunistically evaluate all of the opportunities that we see based on 2 very simple tenants: #1 is the Science Beautiful. Can we effectively connect the dots from genetic algorithms all the way through to symptomatology and target the well-described disease at its source with a hope to actually be disease modifying. And secondly, is it NPV positive? Because we're trying to create a business that starts very early and ultimately takes products all the way into the marketplace and does that sustainably over the next couple of decades. So we can't ride a high bubble or we can't ride diseases that are inherently NPV negative. We want to look at the cases where the science is both beautiful and where we've got NPV positive opportunities. But beyond that, we're not going to focus specifically on an individual therapeutic area. In fact, we're going to cut across 8 and a growing number of therapeutic areas. We're not going to look at a specific disease, but we're actually addressing 20-plus diseases, and hopefully, that number increases over time. And then we're not going to use specific modality. We're actually going to use 3 modalities or 4 as we have in our repertoire today, and that number will likely increase as well. So we issue this didactic narrative-based company build. And rather, we say, we're going to play in this advantaged space. The question then that comes next is how big are you going to play in this space? And our aspiration, as I mentioned from the get-go, is to play as broadly as possible as long as their lives innovation that's [ Monsalo ] in these academic labs that we think could help patients and that represent beautiful science and that are NPV positive. And so how do we scale a system like that? How do we scale a company like that? We learned a bit about that from one of the best books that we read last year for sure by Geoffrey West entitled, Scale. And there's a lot of learnings to pull out from this book. Two of the very simple ones; deal with scaled systems that grow super linearly. And I'll just recite the rules. First of all, that systems that grow super linearly often have simple rules repeated at many different levels. By the way, that's true. Most emerging systems, it's actually -- one of the definitions of emerging systems. It is also how life and genetics and genetic systems work. So that's not surprising, but interesting. And the second is that systems that goes super linearly tend to be decentralized versus centralized. So what do we do? Number one, we establish simple rules that apply anywhere within the context of BridgeBio. It doesn't matter if you're working in an affiliate, on a specific disease or essentially within our infrastructure, we put patients first. We think independently and let science speak, and we try to be efficient, both in the context of temporal efficiency as well as cost efficiency. We marry that with a fully decentralized approach, trying to preserve what we see as the advantage of biotech versus big pharma, which are the diseconomies of scale that are inherent in productive R&D. So we have small teams that focus the level of each disease and each asset. They are represented by our affiliates, and we hook them up to a centralized infrastructure that promotes efficiency, allows us to cut where we're not doing well and double down and learn from our successes over time. That is a fully realized system that can scale super linearly and not sublinearly over time, taking advantage of returns to scale and not economies of scale. So what does that look like? And have we been doing that over the course of the last 5 years since our inception? The first way you might think about that is this slide, which is how we've grown over time, both in terms of number of new programs, and progress within our pipeline. This is sort of the obligatory arrow slide, I don't like it much because the growth from 0 to anything is obviously huge. So from the start, yes, we've grown. But I think the better way to think about this in terms of returns to scale is what we've accomplished over the last 12 months. Lots of investors have been asking us, well, what have you really done since you IPO-ed? And this is just a brief list of what we've accomplished. Number one, we filed an NDA. We have another NDA that we are filing in second-line cholangiocarcinoma, where we have ODD fast track, where we've been invited for ROTR and project Orbis. Obviously, 2 small markets, but demonstrating that we can start to really execute all the way through the finish line of an NDA and start to think about how we market these drugs. We filed 7 INDs. We've initiated 6 new clinical trials to bring the total to 16 across 350 different trial sites in 25 different countries. And I'll talk a little bit more about that when we talk about our product platform. We've announced 8 new programs into -- including 2 key ones, actually in LDMT2I, which is a big disease and ADH1, which is one of our key catalyst drivers where we just announced the initiation of our Phase II clinical trial. And most importantly, we started to put out data that matters. We had some pretty interesting data around our ATTR cardiomyopathy program last year in AHA. We showed dose-dependent increases in collagen VII against dystrophic epidermolysis bullosa program a couple of months ago. We've shown preclinical but interesting data in the context of general adrenal hypoplasia and Canavan disease, in the first case, showing that we have a durable, both MRNA, BGC counts and now protein expression in the adrenal Cortex and in the latter case, showing that IV ROA is as effective. It's not more effective than other ROA alternatives. In achondroplasia, we've continued to present data that suggest that we might be able to have assets for these [ kiddos ] beyond just AGV and into things like spinal stenosis, chronic pain, proportionality and several of the other aspects of the disease that they have to deal with. And we had an interesting note in Journal not long ago about our FGFR inhibitor in the context of FGFR1-driven tumor induced osteomalacia. And this is just a smattering of the overall amount of activity that's ongoing to progress our pipeline forward. So it does feel for the first time really that we're seeing increasing returns to scale. And that, I think, is a product not only of repeated application of our product engine but also our ability to start to operate at a high level and not make as many mistakes as we were making when we started out as a company. All right. So that is really the strategy and the underlying organizational principles. What is the platform or product engine that lies on top of that look like? I'm going to spend the next couple of slides discussing that. We term our product engine, discover, create, test and deliver. Maybe the words aren't that innovative. But certainly, I think what we're doing is interesting to us. Discover is how we found those 8 new programs in the last 12 months. Create is how we filed those 7 INDS. Test is how we're running those 16 clinical trials. And deliver is the burgeoning commercial apparatus that we're putting together that now transitions us from, say, economies or diseconomies of scale and R&D, to the economies of scale commercial world. But we imagine that in the context of orphan disease where a call point may not be as important as several other central capabilities like market access, patient hub services and the like, and I'll talk about that in a moment. I'm going to step through each one of these aspects in our product engine because I think they're important to talk about. Discover really starts with 3 different elements, one of which we've talked about quite a bit over the course of the last 5 years, but a couple of the others that we've built out more recently. One that's been more recent, I would say, in terms of a real strength for us is our computational genomics and statistical genetics group. We've finally gotten access to many of the large databases that are genetic out there. We used to just sit on top of home bar and clean bar, but now we gained access to the U.K. database in Finjan, et cetera. And we can do de novo target discovery, and we can also do quite a bit around target validation and indication expansion. Taking that theme that we talked about earlier of -- let's say, we have a homozygous recessive disease, might there be heterozygous function patients out there where a drug might be useful for them. Those are the types of queries that we can run now at large-scale and pretty rapidly with a team of statistical geneticist. The second piece of this platform within Discover is one we talked about quite a bit, which is a bottom-up mapping of the 7,000 or so Mendelian diseases to say which of those diseases are truly well characterized? Where can we go from genetic aberrance to protein aberrance and quantitatively map this thing all the way to symptoms? We got 14-day criteria that help us to determine whether the disease is useful to go after and whether or not we can make a real difference in patients' lives by targeting the disease at its source. And then the third piece of this platform are our 15 current partnerships with a variety of different children's hospitals as well as cancer hospitals that allow us to support the research that really is the bedrock for our company. Again, we're not trying to innovate every insight into these genetic diseases. We're trying to partner with these great academic institutions to turn their insights into medicines that matter as quickly as possible. And the more we can get in early with these institutions, the more we can not only support their activity, but also efficiently work with them when an insight has been arrived at to start on a therapeutic program. I would be remiss in not citing the people that really help us and drive a lot of this activity. Many of them who are my mentors and we're cofounders of BridgeBio from the get-go. Charles and Frank were 2 cofounders. Charles was my mentor at serve venture. We put together a GBT. He and I worked on Ocado together, and he's really been a driver and leader in this area of Mendelian and genetic disease. Frank was performance similarly was on the SAP at ventures, really thinks very carefully about precision oncology, leads our oncology efforts and leads our key [ KRAS ] and GPX4 efforts that you'll hear about later today, he's also just a wonderful mentor and friend. Richard Scheller, the former Head of R&D at Genentech and then 23andMe, is our Chairman of R&D, oversees a lot of our target speaking and target evaluation activities and is very deep in the science of both CNS diseases, which are very important in terms of have loans sufficient, the next really frontier, I think, in the top 20 or 30 Mendelian disease market of size, but also elsewhere, has been a remarkable mentor. Leonard Post, who is the former CSO of BioMarin and Phil Riley, who I had the pleasure of working with at Third Rock and has really been a pioneer in the area of gene therapy and is very involved in the gene therapy aspects of our portfolio. So these folks come together to help us to evaluate targets, to surface new targets. They know a lot of academics that are working in the area and ultimately, to look to evaluate the progression of our pipeline. And how does that pipeline progress? Well, that's within the next part of our drug discovery and development platform, which we term, Create. The Create element here deals with how we go from hypothesis to actual drug that moves into the clinic. And we have 4 different modalities. We span across medicinal chemistry, therapeutic proteins, gene therapy and antisense oligonucleotides, which is an early but growing area of interest for us. Let me start with medicinal chemistry. Not only do we have folks like Robert Zamboni and Elad Wallach, it's people who sort of see the matrix, which is important when it comes to medicinal chemistry, often individuals, which I'm a big believer in generally, are much more effective when you've got these superstars than broad teams. And these folks really are able to see -- have from going from a hit to lead all the way to an optimized lead and ultimately to development candidate in ways that few others are. They're [ moving ] by a set of infrastructure that I think we don't talk about that often, but it's interesting. Screening infrastructure. We work with the third largest computer in the world to do molecular dynamics. We are doing quite a bit of cryptic binding site analysis in the context of our RAS program. We have orthosteric and allosteric screening programs. We've done a lot of topical formulating, especially around our derm programs. And what we find are small molecule programs are very interesting in the context of Gain-of-function mutations, of which there are many in the genetic disease world, when we can knock these things down and go after that with a precedented modality. Therapeutic proteins, obviously, of interest when you've got an extracellular protein that's missing. And we've built out a core expertise here in large protein manufacturing, mostly around our collagen VII replacement program. If that works, there are several other programs that we've been looking at, that I think we can kick off. We'll have to wait to see whether or not we're getting true functional improvement with these patients. But a lot to be optimistic with, with the recent [ EIA ] data that we released. And this is a team that I think can expand and has the bandwidth to expand well beyond dystrophic epidermolysis bullosa. Gene therapy is a large team now working across 3 disclosed arenas, and -- but you can expect more to come, obviously, replacement of intracellular proteins and loss of function diseases. And I think, importantly, working on the second largest gene therapy market, in my mind, which is congenital adrenal hyperplasia. And then finally, like I said, an ASO technology suite that we're building out, really to focus on diseases of [indiscernible] deficiency, doing some of the things that people have talked about in terms of upregulating the expression of genes of interest. But I think taking a couple of novel approaches to it, and then we'll have more to say about that in the months to come. So that is the Create suite. It's really the heart of what we've put together here at BridgeBio together with Discover. It's what we started with. So I'm glad to see that we filed them of 15 INDs now over the class of last 5 years. It's sort of what we do. The next piece of the product platform is one that we've built out over time. Before I leave Create, I guess I'll just mention some of these folks as well. I won't, in the interest of time, go through all of them. But individual superstars matter when it comes to drug discovery, especially. And you can see that we're privileged to be working with many of them with over 100 INDs and 20 NDAs to their name. These are people that have taken real drugs, not just hype all the way to the marketplace. So what do we do after we've filed an IND? That was a question we asked ourselves early on. And again, we've been very privileged to put together a team of experts. You'll hear from 2 of them later, Jonathan and Susan, on 2 separate of our programs that have helped to build out our development strategy capabilities and our clinical operations into what was once kind of a, can we do this, to now, I think it's an area of excellence for us. Part of that excellence comes from operational execution across these 16 trials that allowed us to build up a database to say, hey, University of Michigan versus University of Minnesota. This is how long it's going to take to turn around the contracts. These are the right CROs to work with the different geographies. This is how you conduct a remote SIV versus an in-person SIV, et cetera, et cetera, et cetera. I think we've got the ability to shave weeks, if not months, off of a variety of Phase I, II clinical trials, which will make us the best owner of these assets as we move into the clinic because time -- and obviously, time especially is critical when you're talking about these large patient unmet needs. And also getting enough patients into these trials, where you've got massive amounts of variance for small patient populations in the endpoint to the ability to really scale those trials out, through great clinical operations, I think, is going to be important. So a lot of what we've done and actually learned through COVID-19 and some of the remote strategies that we've used will be important. Separately, our regulatory strategy and development strategy in a variety of therapeutic areas makes us both uniquely positioned, I think, to execute a variety -- against a variety of different diseases. It puts us close to the agency through a variety of different groups. But it's also taught us some common themes in and around things like natural histories and how we use those as we talk to the agency, how we partner with patient advocates and KOLs in disease spaces where our trial has never been run before. So there are some commonalities as well that we can apply. This is a -- this is the part of our platform, I think, that has been growing most rapidly and is most interesting to think about in terms of returns of scale. And then the final piece is a part of the platform that I mentioned at the outset that we're just building out. And this has to do with commercializing our assets. We're going to start with 2 small ones before, hopefully, where -- we've given the opportunity to commercialize the big one in TTR and then ACON and NCH and then ADH1, which are all very large markets. And one might ask, what is the thing that would make us the best owner of those assets, at least within the United States? And I think it's not call point. I think it is things like understanding how to execute diagnostic partnerships, implement disease awareness strategies, think about market access, patient assistance programs, hub services, distribution, things of that, RCCL, mat out and together with several of our Board members who have commercial expertise. And we've really been trying to build in that area over the course of the last year will help and guide us to build out what, hopefully, will be a part of our platform that operates at scale and with excellence. So that's the final piece of the platform. And this is just another cut of what the platform's been delivering over time. So as I mentioned, over 10 INDs, 20-plus disclosed program, 16 clinical trials and 2 product launches expected next year. And my hope again is that you are going to see year-on-year returns to scale, which means exponential growth or at least greater than one if you go grasp the log of any of this output against the log of time. So that is really what we're aiming for over the course of the next 5 to 10 years. All right. I'm going to end with a brief review of our products, and this is really going to stem into the rest of the day where a variety of folks will take you through -- experts that are much deeper than I on the specifics of each on of our product programs that are either best-in-class or first-in-class in some very large opportunity areas. Let me start with the manifestation of all of the product engine activity that's ongoing, which is our pipeline. It's currently disclosed today. I'll just make a couple of comments that are interesting as we think about strategy. Number one, when we set out, we didn't say we wanted to just work on large diseases or small diseases. We didn't just say we wanted to work on TA of the certain sort. Obviously, we stayed opportunistic, as I mentioned. And this has come together in a rather opportunistic like pipeline. We have several large markets and some small markets, all of which are NPV positive, we believe. All of which have a great opportunity to help patient populations, some of which are small, some of which are large, and all of which target well-described genetic diseases at their source. And the diaspora of what's been presented here also relates back to our product engine, which, as I mentioned, cuts across a variety of different modalities, both late stage and early stage. If you flip to the next slide, you can see the 4 key products that I think investors are very focused on over the course of the next 12 to 24 months. Again, the opportunity to be best-in-class or first-in-class in some very large disease markets and try to do something profound for patients by targeting these well-described diseases at their source. I'm not going to walk through each one of these. There's time for that later in the day, and I'll give a recap at the end. But I'll just mention the fact that you can see the opportunity size [Audio Gap] the upcoming events are seminal. They're either Phase III readouts, where we will show real effect on feeling better or mortality. And on the flip side, there are proof-of-concept data points that will show effect against what we think to be a registrable endpoint for those Phase IIIs. So big unmet needs, and I think we're going to learn a lot about these programs. And you, in turn, will learn a lot about how good we are or bad we are by picking products. My hope is that on a risk-adjusted basis, we do quite well here. These all programs make sense quantitatively and qualitatively, but that will be a good judgment, I think, over the next 18 months. The obligatory investor slide as it relates to the large opportunities here. Again, opportunistically, we've worked our way into several disease markets that have high numbers of patients, which often then relate back to the fact that these are billion plus dollar market opportunities. Several of these are untargeted oncology, which does make sense. Some of them are in the rare -- there are maybe 20 or 30 Mendelian diseases according to our market mapping that really will be billion plus dollar opportunities, and we're playing in at least 3 of them. So that's of interest. And I think we continue to play more of them over time because we sense that the science is ripening in some other large areas in the top 20 or so genetic diseases. We also believe, by the way, that some of our small opportunities that are high POTS added up, could act as synthetic blockbusters. And so that's not -- those aren't spaces that we would sacrifice in lieu of some of these large markets. We think the company can actually execute both together, which speaks again to the scale aspect that we spoke about. And I'll just wrap up here by going all the way back to the beginning by saying, we really are a company that seeks to partner and work with real experts in each one of these disease spaces. It's why we exist. And we're really inspired every day by these partners. I'll just start from the top. You're going to hear from all these folks today, Ravi, who has been inspiring, both clinical geneticist and clinician, who's taken care of Kiddos with achondroplasia, as well as several other folks in various skeletal disease areas. And we've learned a tremendous amount from him, both around achondroplasia as well as other programs that we'll be working on and speaking about in the near future. And Julian, who has been just a tremendous advocate for TTR patients, both in terms of being a physician and a physician researcher as well as being a diagnostician, and he's helped us tremendously to understand TTR Amyloidosis as it relates to cardiomyopathy in the context of the disease mechanism as well as in the context of clinical application. Kiki, who's working on one of our more exciting programs, I think, our first gene therapy program in a large market in congenital adrenal hyperplasia. And Michael Collins, who's, I feel like working across at least 4 or 5 bridge filed programs, will be talking about one in ADH1, where we recently announced the onset of our Phase II trial. He has been a real inspiration to many of us as he seeks to apply lessons from genetics across a broad diaspora of patients that he sees in a variety of different areas like bone disease. And then finally, you'll be hearing from our very own Frank McCormick on our efforts in early-stage targeted oncology, which will be quite exciting, I think. So let me stop there and turn it over to our next speaker and have Christine introduce them, and thank you in turn, for your time.

Thank you, Neil. [Operator Instructions] I'd now like to turn it over to Susan Moran to introduce our achondroplasia program. Susan is the Chief Medical Officer of QED, a BridgeBio company developing infigratinib for achondroplasia and FGFR-driven tumors. She has over 20 years of experience leading clinical trials, including the successful approval of NERLYNX. She previously was the VP and Head of Clinical development for Puma Biotechnology and held senior positions at Millennium and Genzyme.

Good morning. It's a pleasure to be here and participate in this virtual R&D Day. So QED Therapeutics is developing infigratinib for FGFR driven conditions, including development of very low dose infigratinib for treatment of achondroplasia. Achondroplasia is the most common cause of disproportionate short stature. And in fact, it is one of the most common genetic conditions with a prevalence of over 50,000 individuals in the U.S. and Europe alone. Achondroplasia is uniformly driven by activating mutations in the FGFR3 gene with over 95% of cases caused by a single point mutation. Although it can be genetically inherited in an autosomal dominant fashion, 80% of instances arise from new spontaneous mutations. And what that means is that 80% of babies born with achondroplasia are born to 2 average [ Achondroplasia ] patient parents. Preclinical data suggest that infigratinib by directly targeting the abnormal FGFR receptor can normalize the signaling pathways and potentially address the clinical issues that occur with people -- in people with achondroplasia. So we understand this condition well at a molecular level. The abnormal FGFR3 receptor activates 2 downstream signaling pathway, MAPK and TAK1 which together result in abnormal growth plate development and can cause the symptoms we see in people with achondroplasia. So of course, short and stature, but more importantly for health, there can be defects in the spine, so there can be a narrowing of the spine called spinal stenosis, which can ultimately lead to chronic pain in adulthood. We can also see the foramen magnum, which is the opening at the base of skull through which the spinal canal passes, that can also be tightened and foramen magnum stenosis can lead to neurologic emergencies and children that would require emergency neurosurgery. In addition, foramen magnum stenosis has been associated with sudden infant death. We believe infigratinib, as an orally available FGFR inhibitor, has the potential to be the best-in-class approach by directly inhibiting the overactive FGFR receptor, locking the up-regulated TAK1 and MAPK signaling pathway, which would ultimately allow for reversal of the key driver of symptoms. Preclinically, we have evidence of efficacy for infigratinib to positively affect the achondroplasia phenotype and a validated achondroplasia mouse model, we have seen positive changes in the cranial bones, so an increase in the foreman magnum area as well as an increase in the length of the skull, which could potentially translate into decreased foramen magnum stenosis. In the spine, we see an increase in the vertebral length and an increase in the intervertebral disc width as well as normalization of the architecture of the spinal canal, which could translate to a lower rate of spinal stenosis. And then finally, of course, we see increased links of long bones. The mouse studies have also been repeated at lower doses of infigratinib, and we see a robust dose-response relationship for infigratinib effects on bone growth and development. This table presents preclinical data for the therapeutic agents currently in development for achondroplasia. Each therapy in development has been analyzed in an achondroplasia mouse model. The top 3 in the same mouse model and then the bottom Pfizer agent in a slightly different achondroplasia mouse model. Of course, none of these agents have been prepared directly in the same experiment. But we believe infigratinib has the best mechanism of actions of the achondroplasia treatments and development and potentially the best-in-class preclinical profile. In addition, you'll notice that it's the only oral agent in development. The other agents currently in development all require either a daily or weekly subcutaneous injection. Now it is my pleasure to introduce Dr. Ravi Savarirayan, Professor of Clinical Genetics at Murdoch Children's Research Institute in Melbourne, Australia. He's the Foundation Director of the Southern Cross Bone Dysplasia Centre and the immediate past President of the International Skeletal Dysplasia Society. He also happens to be the lead principal investigator of our PROPEL studies to examine the effect of infigratinib in children with achondroplasia. He'll be discussing some of the important clinical implications of achondroplasia as well as touching on our clinical development program for infigratinib in achondroplasia. Ravi?

It's nice to be here today. I'm sorry, I can't be here in person with you for this R&D day for BridgeBio. So I'm going to take you through over the next 10 to 15 minutes the condition of achondroplasia and the issues around health and the key issues that I and other medical doctors see as the unmet needs in this condition. It's important to realize that some people with achondroplasia have no or minimal medical issues, but most have a variety of medical problems across the lifespan and almost all have the potential for medical issues. So I guess the goal of treatment for me as their treating physician is to give families options to decrease their medical burden of their condition over the lifespan. And we want to aim to detect them early and to intervene to either prevent them or stop more serious damage. It's also important to know that disproportionate short stature in itself can impact significantly on quality of life and does matter to psychosocial well-being. And we actually need better tools to evaluate the condition, its complications and the quality of life issues as well. And obviously, as we move forward in this era of therapy for achondroplasia, we need to engage productively with our consumers, our partners in short stature communities as new treatments emerge. So what are the medical complications of achondroplasia? A lot of people are actually confused because they talk about achondroplasia as only being an issue for height. That is not correct. And you can see there the litany of medical complications that affect the large proportion of individuals who have achondroplasia. And these can be as significant as the 50x relative risk of sudden infant death like syndrome in the first 5 years of life. And this can lead to other significant problems during the lifespan, including spinal stenosis, problems with limb deformity, problems with short stature and its impact on function and its impact on pain. So it's really, really important. And I guess as the lead investigator for this trial and many other trials in this field, my aim is to decrease the risk of these complications in children with achondroplasia so that they can live healthy lives and not have to come and see me in hospital. That is the bottom line on why we are doing this work. Some of the major issues I want to highlight today briefly, the first of those is the foramen magnum, which you can see is the big hole where the brain becomes the spinal cord. In 100% of individuals with achondroplasia, this is significantly narrowed. And it's a major issue, which we believe it contributes to a high incidence of infant mortality because it compresses the very vital brain structures that goes through there, including the respiratory center. And there really have been no consensus on the guidelines and evaluation of this complication around the world. And in 2015, we wrote some guidelines to try and standardize management, but more importantly, to stimulate further research around this. But certainly, this is an important issue, and we hope that medications that will address the underlying pathology in achondroplasia will address this issue and address some of the important morbidities around this issue. The other issue that is one across the lifespan are spinal issues. Just like the foramen magnum, the spine is stenosed or narrowed in 100% of individuals with achondroplasia at all levels. And this can lead to chronic back pain in children as young as age 10 years. And in many adults, it necessitates surgery, which is actually often not effective. And there have been again controversies in how to monitor, how to assess and how to treat and manage this complication. And surgical management of this complication has often been suboptimal. So I think that, again, this is another important area where people with achondroplasia would like a better treatment than surgery or a better treatment than just accepting the fact that they're going to be in chronic pain as they get older. So this is again one of the areas in which a precision therapy for achondroplasia that treats the spine and that increases the spinal diameter will have benefits for children, but more importantly, have benefits for adults as they progress through their lifespan. And in a recent study done by one of my students in Norway, we think that the prevalence of spinal stenosis causing symptoms and chronic back pain and limiting function could be up to 70% of adults with achondroplasia. So let's hope that any treatment that acts early, we will see a benefit and an investment in health throughout the lifespan and certainly, as these children become adults and progress through their 20s, 30s and 40s. It's very important to remember that pain and function is significantly impacted in achondroplasia and in all conditions that affect the skeleton with disproportionate short stature. Again, there has limited data on the pain prevalence and severity in skeletal dysplasias generally, but Julie Hoover-Fong studied 361 people at the Little People of America meeting some years ago, and it was a cross-sectional online study and interestingly, the highest reported incidence of pain was in the achondroplasia cohort. Approximately 70% of people had pain and 20% of that cohort had little or no functional mobility to walk. So really, it's very, very important that any therapy for achondroplasia looks at how it will change the incidence of pain and increase function and quality of life. And we're hoping that the gains and the improvement in skeletal growth, both of the arms, the legs, but also the spine will increase functional independence, decrease fatigue, decrease pain and improve quality of life. They're all of the knock-on effects that we get. And I guess the endpoints that we're using in many of these studies are height because they're the most reproducible endpoints but they need to be inextricably linked to function, to pain and, of course, to quality of life for our patients. It's also extremely important that we don't ignore the psychosocial aspects of achondroplasia. And I run a lot of focus groups for adolescents, teenagers and young adults with achondroplasia who tell me that, unfortunately, even though we live in a supposedly politically correct world, teasing and cyber bullying is a reality. They have photos taken of them that are then posted on to various social media platforms in a non-positive manner. And I think that's really, really important because this does have a huge impact on these children and their siblings and their parents. And it's important to acknowledge that. And it's important also to acknowledge that in many countries, there are a lot of cultural differences in the way that people with short stature are viewed, in the way that they can access their environment, in the way that can access public transport and the discrimination laws that are there to protect them and their independence. So it's really, really important that we not only concentrate on height and function and pain, we also have to concentrate on psychosocial well-being. And I guess the psychosocial well-being of our community has really been highlighted by this current COVID-19 issue and the fact that psychosocial aspects and the mental health of communities in lockdown has certainly been problematic. And it's very important that support groups, genetic counselors and psychologists are also part of the holistic care of children and adults with achondroplasia. And we need to be acutely aware of the impact of short stature in itself at different ages, both at preschool, in the school and in the community because sometimes an increase in height itself will increase psychosocial well-being, will increase access to the environment and will increase independence in these children. And I think a picture says it better than many words. And so I'd like to share this picture with you with permission of one of my patients who's been in one of the trials -- or one of the many trials I run for children with achondroplasia. And this is a little girl who had been going to camp. Year after year, and she'd been trying to climb this climbing wall at her camp. And prior to this time, she's actually never been able to get off the ground, but partly because of the fact that she's now taller, the fact that she has longer arms and longer legs and is actually stronger, meant that she actually made it to the top of this climbing wall. Now there's not a lot of science around this, but this is what I would like to illustrate is our goal for children and adults with achondroplasia with therapy. It's actually making sure that they can do everything other children who don't have this condition can do, whether that's being able to climb the top of the climbing wall, whether it's being able to access public transport without being carried, whether it's decreasing the chance of sudden infant death syndrome in the first 5 years of life, or whether they can go to Disney world and not be the only one that can't go on that ride because they don't meet some sort of arbitrary height requirement. So I think that this slide is a very important slide for me and I hope for you because it really sums up why we're doing what we're doing. We want children to have childhoods where they don't need to go and see doctors and allied health workers on a regular basis. And actually, as they become adults can do whatever it is they want to do without discrimination and without medical complications hampering those goals. So I'll now move briefly on to the PROPEL clinical program, which is now enrolling. And you can see there, we both have PROPEL and PROPEL 2. So all children that go into the drug study will have been in an observational run-in growth study for a minimum of 6 months to establish their baseline annualized growth velocities and to also collect other data. And the key inclusion criteria to be eligible for the PROPEL study are children aged 2.5 to 10 years old, and they obviously have to have a clinical and molecular diagnosis of achondroplasia confirmed. And the primary objective of this trial is to calculate their baseline annualized growth velocity. And I think that's very important. And I think one of the important things to notice is that we are recruiting children as young as 2.5 years, where we still potentially have the ability to influence those key things such as spinal growth and frame and magnum growth and lay down the foundations that will provide better health for these children as they progress through childhood and adolescents and importantly, into adulthood as well. So I think that's extremely important. And then that will lead into the Phase II dose finding study, which has already commenced. And this will be a dose escalation study, starting off at a very low dose and then dose escalating if things go well and safety is being confirmed. And obviously, with the Phase II study, our primary objective is to identify a safe and therapeutic dose for further expansion into further pivotal starring studies to understand the safety profile of this medication and its tolerability in children with achondroplasia and also its pharmacokinetic profiles and to also understand the change from baseline annualized growth velocity. And then once those things have been established and the dose has been established, that will then lead into a long-term extension study to obviously look at long-term safety and efficacy variables. So that gives you a brief scheme of the types of things that will be occurring or are already occurring and are due to occur in the next 24 months. There are 6 countries around the world participating in this study. And obviously, even though we're the most southern of these studies, we're very proud to be leading this study and working very closely with the people at QED and BridgeBio to being the best trial and the best endpoints to increased health and hit all of those key things I spoke to you about in what I believe is important. And more importantly, what children and adults with achondroplasia would like for better health. So you can see those sites geographically there. I guess the COVID has impacted slightly on this, but we hope that despite COVID, this trial will go ahead. And certainly, in my institution in Australia, these trials have been designated as critical and essential business and are ongoing, which is good to know. So I will stop there, and thank you for your attention. And I guess, the take-home message is that we're really, really in an exciting era where I became a doctor not to preside over illness but to try and alleviate and -- illness and suffering and improve quality of life wherever possible. And I believe that products like this will give families and children with achondroplasia, options for better health. And that the trials that we're embarking upon will rigorously test the safety and efficacy of these options so that they can be a different option for children. It doesn't take away all the other things we need to do with increasing society's awareness of disability, increasing laws, increasing the accessibility of our environment through architecture, but it's also very important that we have disruptive medications to offer children and adults, better quality of life. So I thank you for your attention.

Thank you, Robbie, for that compelling overview of achondroplasia. We're now going to transition discussing our program for ATTR. I now have the privilege of introducing Jonathan Fox, our Chief Medical Officer for Eidos and Head of Cardiorenal diseases at BridgeBio. Jonathan was previously the founding Chief Medical Officer at MyoKardia and held senior positions at SmithKline Beecham, Merck and AstraZeneca. Jonathan?

Thank you very much, Christine, and thank you, ladies and gentlemen, for joining us today in our virtual R&D Day. My name is Jonathan Fox. As Christine told you a little bit about me, and I'm here to tell you about our transthyretin amyloidosis project acoramidis for ATTR. In this project, we're seeking to address a large and growing need in ATTR, a progressive and fatal disease affecting over 400,000 patients. It's designed to target the disease at its source by stabilizing TTR, a genetically and clinically validated mechanism. We're advancing acoramidis, a potential best-in-class drug that mimics a naturally occurring rescue mutation. Acoramidis has been well tolerated and demonstrated near-complete TTR stabilization in Phase I and Phase II clinical studies. We're currently executing a Phase III study in cardiomyopathy, with top line data expected in late 2021 or early 2022. Acoramidis was designed to treat ATTR at its source. According to this cartoon of the disease mechanism, native TTR circulates in the blood as a tetramer or 4-part complex of 4 identical subunits. As you move across the first row of this diagram, we can see that there are at least 130 known destabilizing or pathogenic mutations in the TTR gene. And that, in fact, there's also a protective mutation that we mentioned in the prior slide, the T119M mutation that can prevent the development of disease in people carrying such a pathogenic gene. It disassociates -- the tetramer disassociates into monomers, initiating the pathogenic pathway of the disease as those monomers misfold, aggregate and are deposited in affected tissues causing the symptoms and progression of the disease. Our therapeutic hypothesis is that by binding an effective stabilizer like acoramidis, which was designed to mimic that protective T119M mutation, it stabilizes the tetramers to slow or halt disease progression. As I mentioned, acoramidis has been generally well tolerated and demonstrated near-complete TTR stabilization in preclinical Phase I and Phase II studies. On the left-hand side of this slide, we see a safety summary from the Phase II program. There were 49 individuals who participated in the blinded randomized portion of the study with 17 allocated to placebo and 32 allocated to active dose, 2 doses. You see then the table showing any adverse event in any serious adverse event, which was generally well balanced between the placebo and active arms and in fact, favored the active arms in terms of the percentages of people experiencing adverse events and the types of adverse events and their severity or seriousness. On the right-hand side of the slide, we see a representative display of data from one of the TTR stabilization assays that we used. And you see that even at trough, that is to say, the blood level of acoramidis prior to the next dose at steady state, there was 100% stabilization by that asset. The ATTRibute-cardiomyopathy study, which is our Phase III study that is ongoing will provide 12-month functional outcome data and 30-month mortality and cardiovascular hospitalization data according to the schematic. You see the key inclusion criteria listed on the left-hand side of the slide. These are basically people who are diagnosed with ATTR cardiomyopathy, either wild-type or mutant TTR gene carriers. And they are -- fall into the New York Heart Association functional classes 1 through 3. They can be have -- they have can -- have had their diagnosis established either by a positive biopsy showing ATTR or through the noninvasive diagnostic algorithm that was published in 2016 by Gillmore et al. that relies on a technetium bone scan plus exclusionary tests for light chain amyloidosis, which can also mimic this disease. You see in the middle, the timescale of the study that is -- randomizes a total of estimated 510 people, 2:1 to active versus placebo. And at the 12-month time point, we'll have a readout on 6-minute walk distance change from baseline. And at the 30-month time readout, we'll have all-cause mortality and cardiovascular hospitalizations analyzed by a modification of the win ratio approach. ATTRibute-CM is designed to evaluate the safety and efficacy of acoramadis across a series of complementary measures of both drug activity and ATTR cardiomyopathy disease progression. We'll be measuring TTR stability by the 2 established assays of Western blot and fluorescent probe exclusion. We'll be analyzing disease biomarkers of serum TTR, N-terminal proBNP and Troponin I. We'll be assessing functional outcomes and quality of life using 6-minute walk distance and the Kansas City Questionnaire. And then morbidity will be assessed through the frequency of cardiovascular hospitalizations and mortality assessed by any cause, as you can see listed in this slide. Again, there is Part A primary endpoint after 12 months and the Part B primary endpoints after 30 months of therapy. We know from natural history studies and placebo arms of other studies that have been completed that there's a rapid functional decline in untreated ATTR cardiomyopathy patients providing an opportunity to demonstrate a robust clinical benefit even after 12 months. You can see that this graph is a composite of some natural history studies, the tafamidis ATTR-ACT study's placebo arm and the tafamidis ATTR-ACT active arm. And so an optimal profile for acoramadis would markedly slow or halt decline in the 6-minute walk distance in trial participants, as you can see in this display of data. The Part B endpoint will hierarchically compare mortality and cardiovascular hospitalizations between all pairs of trial participants. So this schematic, on the left-hand side, you can see that the approach of the Finkelstein-Schoenfeld modification of the win ratio analysis pairs each participant in the active group with each participant in the placebo group, generating a series of wins or losses, as you can see, displayed in the schematic on the right-hand side of the slide. So every time there's a pair-wise comparison, first it examines all-cause mortality. And if the patient or the participant either died before someone in the placebo arm, that's a loss. If they died a -- later than the other participant, that's a win. And if they didn't die at all and the other patient died, that's also kind of as a win. If the mortality event occurred exactly at the same duration of treatment, that's a tie, and then it moves on to the same kind of pair-wise comparison of the frequency of cardiovascular hospitalizations. So in that way, you generate a hierarchical series of wins and losses that is then tabulated to give you the final data results. So to summarize the overall program, we have ongoing and planned studies of acoramadis and the aim is to continually expand the clinical evidence database and addressable patient population, first through the study that I just summarized for you, ATTRibute-CM. We're also launching a program in polyneuropathy, the ATTRibute-PN study. And we have plans in the works now for a series of studies to follow on from these registrational studies that will continue to expand our knowledge of how to best diagnose these diseases and how to better treat them. I'd now like to introduce Professor Julian Gillmore, who is the Centre Head at the University College London Centre for Amyloidosis & Acute Phase Proteins. Professor Gillmore's research interests include the pathogenesis, diagnosis and treatment of amyloidosis. He's the co-author of over 250 peer-reviewed articles including numerous regarding ATTR, and he's also the Co-Chair of our ATTRibute-CM Steering Committee. Professor Gillmore, over to you.

So thank you very much for the introduction. It's a great pleasure to be here at this BridgeBio R&D Day. So I'm going to talk to you about the epidemiology and clinical features of transthyretin, otherwise known as ATTR amyloidosis. I'll talk a bit about the diagnosis and staging of cardiac transthyretin amyloidosis and then touch on the treatment principles in amyloidosis, generally with a particular focus on ATTR amyloidosis. So amyloid is an abnormal extracellular misfolded fibrillar protein deposit in tissues, which is characterized by its pathognomonic green birefringence when the tissue is stained with Congo red and viewed under cross-polarized light. There are, in fact, more than 30 different proteins that conform amyloid fibrils in humans, and they form the basis for the classification of the different types of amyloids. So for example, in AL amyloidosis, the fibrils are composed of monoclonal immunoglobulin light chains. In AA amyloidosis, they're composed of amyloid A protein. And in the condition we're talking about today, they're composed of either wild-type nonmutated transthyretin or alternatively mutated transthyretin. It is important to determine what amyloid type one is dealing with in clinical practice because the different types of amyloidosis behave very differently, and they're treated in a completely different manner. So wild-type ATTR amyloidosis, as I mentioned, the amyloid fibril protein is unmutated transthyretin. It's essentially a cardiomyopathy, and it's an increasingly recognized cause of heart failure in individuals over the age of 50 and particularly males. It's a progressive and fatal condition within 3 to 10 years. There are some extra-cardiac features, which typically include carpal tunnel syndrome and lumbar canal stenosis. Interestingly, autopsy studies indicate that cardiac ATTR amyloid deposits are present in 25% of males over the age of 80. And a vast majority of those individuals are not diagnosed with amyloidosis, the clinical disease, in life. And that highlights: one, the poor sensitivity of echocardiography, we know lots of these patients never get diagnosed despite having a significant cardiomyopathy; but it also calls into question the clinical significance of amyloid deposits. Are there a whole bunch of individuals who have amyloid deposits with no significant cardiomyopathy? The panel at the bottom on the right, there, you can see the massive increase in the number of new diagnoses of cardiac ATTR amyloidosis in the U.K. from our national center and this is true all over the world. The -- particularly in wild-type ATTR amyloidosis, the line shown in red there. Hereditary ATTR amyloidosis, the amyloid fibril protein is mutated transthyretin, is dominantly inherited, and there are, in fact, more than 130 amyloidogenic mutations that are known about of the TTR gene that cause this disease. The phenotype is characterized by cardiomyopathy, just like in wild-type ATTR amyloidosis, but patients with hereditary ATTR amyloidosis often have neuropathic involvement, both peripheral and autonomic neuropathy. And when they have both cardiomyopathy and neuropathy, they're known as having a mixed phenotype. The commonest variance that we see in the U.K. and also in the U.S. is the V122I TTR variant, which is actually present in 4% of African-Americans or Afro-Caribbeans. And that is certainly a major susceptibility factor to getting predominantly a cardiac phenotype of ATTR amyloidosis. The other variant that we see in the U.K. and is also prevalent in the U.S. is the T60A variant, which is originally from Ireland and is associated with a mixed phenotype of both cardiomyopathy and neuropathy. Traditionally, the diagnosis of amyloid required a biopsy and staining of an affected organ with Congo red and a panel of antibodies to work out what type of amyloid one is dealing with. Now as you can imagine, cardiologists rarely perform hard biopsies for patients with cardiomyopathy. And similarly, neurologists fairly -- rarely perform nerve biopsies for patients with peripheral neuropathy. So the other option in terms of a biopsy diagnosis is what is known as a screening biopsy. And historically, that was always a rectal biopsy, but more recently, there's been data on abdominal fat aspirations, which is a very simple technique that can be done in the outpatient clinic. One sucks out a little bit of fat, makes a slide, stains it with Congo red and one can sometimes detect amyloid. But as you can see in the panel on the bottom there, the sensitivity of fat aspirates in ATTR amyloidosis is, in fact, very low. And coupled with the poor sensitivity of echocardiography, in fact, an echocardiogram with -- in a patient with cardiac amyloidosis looks very much like hypertensive heart disease or hypertrophic cardiomyopathy and it's very difficult to distinguish between those clinical conditions, such that the combination of a poor sensitivity or difficulty obtaining tissue, coupled with the problems with echocardiography means that the diagnosis is often missed. Now things have changed in recent years down to really 2 tests. One is cardiac magnetic resonance imaging, or MRI. We first reported a series of 29 patients in 2005 with cardiac amyloidosis and found that they had this very characteristic late gadolinium enhancement. When you inject gadolinium, it doesn't get into cells and the simple reason for this late gadolinium enhancement is the extracellular expansion from amyloid, which means that it takes longer for the gadolinium to diffuse through that extracellular space. And the panel on the right there, you can see that compared to other hypertrophic cardiomyopathies, cardiac amyloidosis is the condition, which really gives the massive expanded extracellular volume and therefore results in this late gadolinium enhancement. The other test that has been revolutionary really in recent years is bone scintigraphy. In the U.K., we use DPD, in the U.S. PYP. And there have been reports in the literature for many years, in fact, several decades, of a patient who has a bone scan has cardiac uptake on their bone scan and turns out to have amyloid. And about a decade ago, Claudio Rapezzi, who was working in Bologna at the time, started to look at this systematically. And he came up with a scoring system and was essentially able to show very clearly that bone scintigraphy is exquisitely sensitive for diagnosing cardiac ATTR amyloidosis. And it was with these 2 tests, in particular, the DPD or bone scintigraphy that we came up in a collaborative study with a noninvasive diagnostic algorithm for ATTR cardiomyopathy. And I'll take you through it. Essentially if a patient that has heart failure and an echocardiogram or a cardiac MRI scan that is suggestive or indicates cardiac amyloid, you can then do a bone scan. And if you have Grade 2 or 3 cardiac uptake, in other words, cardiac uptake that is more than bone, you then exclude the presence of a monoclonal gammopathy using 3 tests, and this is important, you need to do all 3 of these tests: the serum immunofixation, the urine immunofixation and the serum free light chain assay, and if you exclude the presence of a monoclonal empathy using those 3 tests, then you can confidently make a diagnosis of cardiac ATTR amyloidosis. And we were able to show in this study of more than 1,000 patients, which was a collaborative study across several worldwide amyloidosis centers that this noninvasive diagnostic algorithm was exquisitely specific. It was only about 74% sensitive, and the reason for that was the significant proportion of patients with cardiac ATTR amyloidosis had an incidental monoclonal gammopathy. So I'll take you through that with a case. This was a case of a 72-year-old man referred to us with presumed cardiac AL amyloidosis. He was found to have an echocardiogram that was typical of amyloid and a low-level IgA paraproteinemia. When he was referred to us, we found them to have elevated biomarkers. As previously mentioned, he had a characteristic echocardiogram and CMR. He had a Grade 2 DPD scan, but in terms of his clonal dyscrasia, he did have an IgA lambda paraproteinemia. And so he need -- in order to make a diagnosis in this case, he needs a specialized assessment and generally, that means histology, immunohistochemistry or proteomic analysis. So this chap went on to have a fat aspirate as a screening biopsy, but there was no amyloid in the fat aspirate. So he proceeded to an endomyocardial biopsy, which is the target organ biopsy. And you can see there that he has the 3 proteins that identify the presence of amyloid and then the fibril protein was transthyretin or TTR. So this patient had wild-type ATTR amyloidosis. In the context of an incidental monoclonal gammopathy, that was nothing to do with his amyloidosis. Just talking about bone scintigraphy in amyloidosis, it's important, I think, to appreciate the pros and cons, the limitations and the advantages. So if you see diffuse cardiac uptake on a bone scan, you can be very confident that you're dealing with cardiac amyloidosis. If you see no cardiac uptake, however, it doesn't exclude cardiac amyloid. And in fact, up to 40% of patients with cardiac AL amyloidosis will have no uptake on their DPD scan. Similarly, if you see Grade 2 or 3 cardiac uptake, it doesn't prove ATTR amyloidosis until you've excluded that monoclonal gammopathy with the 3 tests that I mentioned. And in fact, about 10% of patients with cardiac AL amyloidosis have Grade 2 or 3 cardiac uptake. So you need to follow the algorithm pretty precisely. In terms of the diagnosis of cardiac transthyretin amyloidosis, data from ourselves, our own center and also the U.S. show this huge delay in diagnosis. And in fact, in our series, which was published a few years ago, there was a median of 17 hospital attendances before a patient was diagnosed with the correct diagnosis, i.e., cardiac transthyretin amyloidosis. And the experience in the U.S. is very similar. Having said that, the panel on the right shows what I think is evidence of an improvement in that regard. So post-2012, the line -- the black line shows improving survival from diagnosis. And in fact, these are patients who did not receive any disease-modifying treatment and the symptomatic management of these patients has not really changed. So while that suggests it's patients post-2012 are being diagnosed earlier. And in fact, post-2012, 70% of patients in our series are diagnosed by noninvasive methods and -- whereas pre-2012, it was almost invariably by endomyocardial biopsy that patients were diagnosed. So I think there is evidence of improvement. There is also a diagnostic delay with the neuropathy or misdiagnoses when patients present with hereditary ATTR amyloidosis and neuropathy. And the average delay in one series was somewhere between 2 and 6 years. And the main differential diagnosis or misdiagnosis was chronic inflammatory demyelinating polyneuropathy. So in order to remain aware of the possibility, one should think is there autonomic neuropathy in combination with peripheral polyneuropathy that certainly suggests amyloidosis in the absence of diabetes? Is there cardiomyopathy in the context of neuropathy, a family history? And if you're in the U.K., is the patient of Irish origin, referring to the T68 variant that I've talked about earlier. If you're a cardiologist sitting in clinic, what are the red flags to make an early diagnosis of ATTR amyloidosis? Well, on echocardiography, certainly looking at strain and seeing abnormal strain, but with relative sparing of the apex of the heart, that is reasonably specific for cardiac amyloidosis. Similarly, looking for the infiltrative features of the hypertrophic phenotype on a echocardiogram can be important. So thickening of the valves, thickening of the interatrial septum and thickening of the right ventricular free wall. And similarly, looking -- asking whether the patient has a history of carpal tunnel syndrome or bilateral carpal tunnel decompressions in the past or symptoms of polyneuropathy or dysautonomia. Those are all clues as to the possibility of cardiac transthyretin amyloidosis. Once the diagnosis is established, you can stage it very, very simply using 2 simple biomarkers, the NT-proBNP concentration and the eGFR. And if they're both favorable, in other words, the NT-proBNP is less than 3,000, and the EGFR is greater than 45, the patient is stage 1. That constitutes about 40% of patients and they survive for about 6 years. If they're both unfavorable, then the patient is stage 3, that's about 20% of patients and the patient survives for about 2 years. And if one or other is unfavorable, then the patient is stage 2, and that's the other 40% of patients who survive for about 4 years. So it's a very nice staging system that is applicable to both wild-type and hereditary ATTR amyloidosis. In terms of staging neuropathy in clinic, we use the PND score, which is a very simple, widely used neuropathy score or the FAP stage, which you can see here how that corresponds to the PND score. For the purpose of clinical trials, various trials have used the various different scoring systems, including the NIS, the NIS-lower limb score, the NIS+7 or the mNIS+7. These are not scores that can be used in clinic. They're pretty complicated. But they're certainly good for evaluating drugs within clinical trials. What do we know about the epidemiology of cardiac ATTR amyloidosis? Well, this is recent data. There's a South Korean study and a Spanish study, showing the increase in the number or the proportion of individuals, healthy individuals that have positive DPD scans or Grade 2 and or 3 DPD scans in the Spanish study with increasing age. You can also see that among patients over the age of 60 who present with heart failure to hospital, 4% turnout to have ATTR cardiomyopathy. And in an American study, 16% of patients undergoing transaortic valve replacement were found to have cardiac ATTR amyloidosis. So that's the emerging data of the epidemiology. In terms of disease-modifying treatment for ATTR amyloidosis or amyloidosis in general, the main established treatment modality for all types of amyloid is to reduce the concentration of the protein that makes the amyloid fibrils. So in this case, transthyretin and that is what the drugs patisiran and inotersen do. They reduce the concentration of TTR in the bloodstream. And the other mechanism for treating, particularly, ATTR amyloidosis is to stabilize the amyloid proteins -- stabilize the TTR tetramer either with tafamidis, acoramadis, as you've heard about from Jonathan or possibly diflunisal. So to summarize, cardiac transthyretin is an increasingly recognized cause of heart failures in individuals over the age of 50, although the true prevalence remains uncertain. Non-biopsy diagnosis is possible in about 70% of patients with ATTR cardiomyopathy, but we need to address diagnostic delays, we need increased awareness and awareness of the red flags. The cardiomyopathy can easily be staged on the basis of eGFR and NT-proBNP. And you've heard about the expanding treatment possibilities for patients with cardiac ATTR amyloidosis, which are really very exciting. We're in a very, very exciting time for patients with a number of treatment possibilities in merchant. So I'd like to thank you very much for your attention and acknowledge my team at the National Amyloidosis Centre who are responsible for generating much of the data that I've presented today. Thanks.

Thank you, Julian, for that overview on ATTR. We're now going to transition to discussing our gene therapy program for congenital adrenal hyperplasia. I'd like to introduce Eric David, who is the CEO of BridgeBio Gene Therapy. Eric was previously the Co-Founder of Organovo and the company's Chief Strategy Officer and Executive Vice President of Pre-Clinical Development. Eric has over 15 years of experience in cell and gene therapy.

Thanks, Christine. I'm Eric David, the CEO of BridgeBio Gene Therapy, and it's my pleasure to give you a quick introduction to our portfolio. We have 2 programs for which we expect to file INDs by the end of the year, BBP-631, our AAV5 program for CAH, which is our focus today. And BBP-812, our AAV9 program for Canavan disease, a rare CNS leukodystrophy. We also have a robust pipeline of earlier-stage programs, including one we've announced publicly, BBP-815, our AAV program for TMC1 hearing loss. Now we're basically a stand-alone gene therapy company that sits within BridgeBio. We're focusing on AAV for the time being, but unlike a lot of other gene therapy companies, we're agnostic to therapeutic area. We go where the unmet need is and where we see great science being done. We have a very flexible and streamlined model that allows us to source programs from leading academic collaborators, do basic science, research-grade manufacturing and tox-grade manufacturing and vector optimization in our 15,000 square foot lapse in Raleigh, so that we can get to proof-of-concept in animals quickly. We have a deep CMC team with decades of experience in gene therapy and vaccines from Novartis, GSK, Bamboo, Pfizer. We do our process development and analytical development in-house so that we can hand over to our CDMO already fully optimized. This not only allows us to achieve best-in-class yields but also saves a significant time and money versus outsourcing PD and AD. Our dedicated suite at Catalent allows us to do multiple 500-liter triple transfection or baculo runs across any of our programs. And we have clinical and regulatory teams with deep experience. Our senior leaders have 10 INDs and 5 Breakthrough or RMAT designations in rare diseases and gene therapy from places like BioMarin, Voyager, Bluebird, Novartis and others. And we have partnerships with leading gene therapy pioneers such as Guangping Gao at UMass, Jeff Holt at Boston Children's and Xandra Breakefield and Casey McGuire at Nash General. Now when Neil asked me to lead BridgeBio Gene Therapy, the only program was the CAH program. And I have to say I was initially a little bit skeptical. Why develop a gene therapy for a disease where the standard of care, corticosteroids, is dirt cheap? But then I started talking to patients and KOLs and very importantly, payers and discovered that this was a disease that has been hugely neglected with truly significant unmet need. Now there are around 75,000 classic CAH patients in the U.S. and EU that even payers understand have been very inadequately served by the standard of care for decades. There's been staggeringly little innovation in CAH since the advent of steroids in the 1950. Yes, so we've seen longer-acting steroids, but little else. There's some innovation now with the development of CRF antagonist. But again, this is more incremental change. But gene therapy offers, for the first time, something that no other therapy can offer. The possibility that we can treat the disease at its source, by allowing patients to make their own cortisol and mineralocorticoids in the right amounts and at the right times, and I believe Kiki will speak to why that's so critical and could be such a game changer for these patients. Now many of you have seen this pathway before, so I'm not going to belabor it. Without 21-hydroxylase, all the progesterone builds up and gets converted to 17OHP and androgens. Even with corticosteroids, patients can still die with renal crisis from something as simple as a mild flu or a bad stomach virus, if they or their parents don't ramp up their steroid dose fast enough. And even with the current standard of care, all age groups of CAH patients have a three to fourfold higher mortality than the general public. They're a full standard deviation shorter than the general public. They suffer from a host of cardiovascular, metabolic and bone and other diseases. Now when you speak to patients, they highlight things that textbooks don't capture. At a patient meeting in 2018, we had an amazing roundtable with adult patients and parents of childhood patients. And they told us all about the profound unmet needs, everything that I mentioned earlier. But they also revealed things that I didn't know. There's one woman in her early 50s who came up to me and said, we read all about gene therapy in the newspapers and I keep thinking when is there going to be a gene therapy for CAH? Because if I could get off steroids or mostly off steroids, for even a few years, that would be amazing. Do you know that I never sleep, most of us don't because steroids keep us up much of the night. And do you know that I'm really old for a CAH patient, but I lived my life like I'm in my 70s rather than in my 50s. Now I just want to highlight a few key data points. We're going after the 75,000 classic CAH patients, but there's a less severe form of CAH called nonclassic that's largely asymptomatic, and most of the nonclassic patients don't require steroids. Those patients have only 5% to 10% of normal 21-hydroxylase activity because this is a very efficient enzyme with a very high specificity for its substrate. So we believe a little enzyme will go a long way. Now in the CYP21 knockout mouse, very low vector doses as low as 0.13 VGCs were sufficient to cure the phenotype. And in NHP studies out as long as 6 months, we saw great durability in VGC, mRNA and protein expression, far above the level needed to cure the phenotype in the disease model mice. Now focusing on that protein expression, we were able to develop a mass spec assay to distinguish the human 21-hydroxylase protein that we were inducing via the gene therapy from the endogenous cyno protein. Now these were normal animals since there's no disease model in NHPs. But even with normal function, we were able to induce at doses as low as 5e12 per kg, protein levels from 9% and up to 24% at the highest dose given of the endogenous cyno 21-hydroxylase protein in the NHP adrenal glands. Now all of those values are within or above the low expression percentage suggested by the genotype/phenotype studies that I showed you on the previous slide, which makes us feel very confident going into the clinic. So with that, it's my great pleasure to turn things over to Kiki Sarafoglou. You can read her bio here. She's one of the thought leaders in the field and has been a PI on adult and pediatric CAH clinical trials, and we're thrilled to be working with her. Thank you.

Thank you for the introduction and the invitation. Today, I'm going to discuss challenges in treating congenital adrenal hyperplasia. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is a part of 6 autosomal types of disorders and it's the leading cause of CAH. In this form of CAH, the enzyme deficiency results in impaired cortisol synthesis, excess androgens production and salt-wasting in 75% of the cases due to aldosterone efficiency. Because of its -- because of the importance of cortisol, adrenal cortisol production is regulated by the hypothalamic-pituitary axis. Normally, when cortisol levels are decreased, it signals the hypothalamus and pituitary to increase the ACTH secretion in order to stimulate the adrenal gland to make more cortisol. However, in CAH, the adrenals are perpetually simulated by ACTH to produce cortisol, which they cannot, so that leads to hyperplastic adrenal and excess production of androgen starting in utero. CAH requires lifelong glucocorticoid treatment and treated or undiagnosed CAH can lead to salt-wasting and/or adrenal crisis, precocious puberty and short stature. And treated CAH children have accelerated growth, which makes them taller than peers their own age when they are young. The problem is they stop growing years before the peers because their bones have fully matured and they end up with short adult stature. Usually, CAH is identified by newborn screening. All 50 states screen for CAH. Once identified, management of 17OHP and androgens confirm the diagnosis. Molecular testing can also be used to distinguishing between salt-wasting and simple-virilizing forms. In childhood, hydrocortisone in 3 dividing doses is the gold star for treatment because it's a short-acting glucocorticoid, which has less negative effects on growth. When growth is completed, many adults opt for long-acting steroids such as dexamethasone or prednisone because they require only 1 to 2 dosing per day. Monitor of the disease control includes measurement of adrenal steroids, electrolytes and renins to be checked in patients with salt-wasting CAH. Monitor of disease control consists of 3 to 4x a year in children and provides limited information, but that's the discussion for another time. Clinical science and symptoms to monitor CAH in childhood include weight gain, growth acceleration, bone -- rapid bone age maturation, to name a few. And in adulthood, again, increased weight gain, blood pressure, osteoporosis and signs of insulin resistance to be monitored. Except for some incremental assessments, treatment for CAH has not had any significant advancements in 60 years. Physicians still struggle to find the right treatment balance to avoid under treatment, which leads to excess androgen production, and overtreatment, which leads to glucocorticoid excess and over suppression of the HPA axis. Because of the limitations of current therapy, patients have alternated periods of hypocortisolemia and hypercortisolemia every day. Chronic hypocortisolemia triggers increased adrenal androgen production, which can then lead to premature fusion of the growth plates, continued genital virilization, precocious puberty, adrenal rests, polycystic ovarian syndrome, infertility, to name a few. Chronic hypercortisolemia because of glucocorticoid excess can lead to osteoporosis, short stature, weight gain, Iatrogenic Cushing syndrome and increased risk for cardiovascular disease in adulthood. Here is an example of what happens in overtreatment and why finding the right balance is critical. In this clinical case, previous providers focus only on normalizing androgen throughout the day, which meant they give you higher doses of hydrocortisone that your body needed. So -- and you can see that she developed Cushing syndromes and increased body hair growth. I must point out that the hydrocortisone doses they gave here were in the recommended rates of daily dosing. However, because this patient was very sensitive to glucocorticoids, even with appropriate dosing, it still caused glucocorticoid excess and cushingoid features. Why is optimal treatment so hard to achieve? Current medications do not replicate physiological endogenous cortisol pulsatile secretion pattern of circadian and ultradian rhythm. Hydrocortisone has a short half-life. Long-acting glucocorticoids lack pulsatility and can over suppress the HPA axis. On top of that, there is a wide individual variability of cortisol pharmacokinetics and the pharmacodynamic response to treatment. And keeping doses within physiological range does not prevent adverse outcomes. Now hydrocortisone's short half-life is even shorter in children with CAH. In this figure, you can see that the normal rates is shaded in gray. You can see that the treatment with 3 doses of hydrocortisone cause supraphysiological spikes in cortisol concentration, quickly followed by rapid elimination with hypocortisolemia between the doses. Most importantly, the evening dose in children washes out in their morning hours, resulting in unopposed ACTH-stimulated adrenal androgen production. Now the rapid elimination of cortisol, we think 6 hours after dosing, as you can see here, causing rapid rebound of the adrenal 17OHP and delta4A concentration levels around the same time. And that's what we saw in a study of 35 patients with CAH. And as you can -- as our 24-hour simulation model based on PKPD parameters of 67 patients with CAH shows that even increasing the number of times that you give hydrocortisone, you can see here 4 times. You can still have periods of hypocortisolemia, and you can see that the adrenal androgen can remain elevated throughout the day. Now another challenge of treatment that is often overlooked is that the normal cortisol metabolism follows both circadian and ultradian rhythms. In a classic circadian pattern, cortisol concentration peak early in the morning and decrease throughout the day, [ within ] it slows the concentration around 11 p.m. in children and midnight in adults. At 2 am, around here, cortisol concentration gradually increase and the 24-hour cycle begins again. It's important to note that cortisol secretion is not continuous. And it's actually derived from a dynamic ultradian rhythm of discrete cortisol pulses, as you can see here, every 90 to 110 minutes that follow ACTH pulses. The upper funnel of the figure shows that healthy controls have a mean number of 12 discrete cortisol pulses over 24 hours. In the lower panel, you can see how circadian rhythm is derived from discrete cortisol pulses, ultradian rhythm, over 24 hours. Now once the time lapses, the glucocorticoid receptors has been so invitro and in vivo in animal models to be of critical importance for gene regulation, nongenomic glucocorticoid signaling, HPA axis regulation and endocrine and behavioral responses. The different and often completely opposite effects of pulsatile versus continuous hormone presentation is well described in other common systems. For example, in females, pulsatile delivery of gonadotropin releasing hormone induces ovulation whereas continuous delivery results in anovulation and suppression of the hypothalamic-pituitary-ovarian axis. Now in collaboration with other Minnesota centers, we collected longitudinal data of over 300 patients affecting with CAH spanning over 50 years. This led to the first study to quantify the effect of hydrocortisone dosing on final adult height. Now this figure illustrates that even hydrocortisone doses in the recommended rate between 10 to 15 mg per meter square per day, a negative effect of hydrocortisone or height it can still be seen, suggesting that other factors such as possibility ultradian and circadian rhythm, timing and frequency of hydrocortisone dose, sensitivity to glucocorticoids, and individual cortisol pharmacokinetics and pharmacodynamics play role in optimal adrenal steroid control and attainment of final adult height. The take-home message is that current therapy does not reproduce endogenous cortisol production rates, nor replicates circadian and ultradian cortisol secretion. However, what current therapy does do is expose patients to alternate periods of pipeline hypo- and hypercortisolemia, all of which result in suboptimal short and long-term outcomes. What is needed to improve outcomes in CAH? You need a therapy that is based on the patient's individual endogenous cortisol production rate and takes into account a patient's individual glucocorticoid sensitivity, and you need a therapy that can replicate both circadian and ultradian secretion of endogenous cortisol.

Thank you, Kiki. We'd now like to transition to our next program, talking about encaleret for ADH1. I'd like to bring back Jonathan Fox to introduce this program. Jonathan?

Thanks very much, Christine. And again, I'd like to thank the participants in today's session for joining us today. I'd now like to tell you about another exciting project we're working on, using encaleret for disorders of calcium homeostasis, including the autosomal dominant hypocalcemia type 1 or ADH1. Encaleret targets hypocalcemia and hypercalciuria by selectively antagonizing the calcium-sensing receptor, or CaSR. This is an opportunity that was identified in collaboration with experts at the NIH, including Dr. Mike Collins, who will be speaking with you after I get done with my part of the presentation. Prior clinical experience enables accelerated development in encaleret. It's been well tolerated in over 1,200 human subjects participating in prior studies for a different indication, except for the side effect or adverse drug effect of a dose-dependent increase in serum calcium, which is the target effect we are desiring in ADH1 patients. In a Phase II study in ADH1 is planned to initiate in 2020 with proof-of-concept data anticipated in 2021. Encaleret has potential to be first-in-class calcium-sensing receptor antagonist with a differentiated profile for ADH1 and hypoparathyroidism caused by other disorders. The initial development will be in the genetically defined population of ADH1 driven by calcium-sensing receptor activating mutations, which are carried by about 12,000 people in the United States. There's the potential for expansion into a larger post-surgical chronic hypoparathyroidism patient population, which consists of about 200,000 patients in the U.S. and Europe. Encaleret aims to treat ADH1 at its source in an almost perfect match between the molecular pathophysiology of this disorder and the molecular mechanism of this drug. The ADH1 disease mechanism, again, is caused by activating mutations in the calcium-sensing receptor. This receptor sits in the parathyroid gland, in bone cells and in the kidney, where it senses the ambient concentration of free ionized calcium and if it's too high, it initiates signals that act to reduce calcium. And if the calcium is too low, it does the opposite. So these mutations make for a hyperactive sensing mechanism that basically tells the target organs of the calcium-sensing receptor that low calcium is sensed as normal or normal calcium ia sensed that is high. So that hyperactive calcium-sensing receptor, as you see in the middle of the upper row of the slide, depresses PTH secretion by the parathyroid gland and increases urinary calcium excretion, causing low blood calcium and high urinary calcium. As calcium levels fall, it requires a massive supplementation in the diet to prevent severe hypocalcemia and the consequences thereof. So the therapeutic hypothesis behind using encaleret for ADH1 is by reducing the sensitivity of those mutant receptors and that is designed to stimulate PTH secretion allowing it to act in its normal way to maintain normal serum calcium, stabilize urinary calcium excretion and avoid the consequences of chronic hypocalcemia and chronic hypercalciuria. These cartoons give you an idea of the molecular pathophysiology of the pathways involved in the calcium-sensing receptor, which acts primarily to regulate both parathyroid hormone secretion by the Parathyroid chief cell and renal calcium reabsorption in the renal tubule. So on the left-hand side, this is a cartoon of a parathyroid gland cell. We see that the calcium-sensing receptor can either stimulate or depress PGH secretion depending on how much free ionized calcium it senses outside the cell. Similarly, in the renal tubule, the calcium-sensing receptor, acts on ion channels in the renal tubular epithelial cell to either allow filtered calcium to continue to pass-through into the urine or to be reabsorbed and brought back into the bloodstream, depending on, again, the amount of calcium that it senses in the blood that's going on. Encaleret is designed to target ADH1 added source by normalizing hyperactive calcium-sensing receptor. So the rationale for studying the calcilytic in ADH1 is because, as I said, it's a perfect fit between the molecular pathophysiology of activating mutations causing a disease and the primer -- prior generation that partially address the ADH1 phenotype despite limited exposure in terms of reducing the sensitivity of the receptor. So in the middle row, you can see that encaleret normalized serum and serum calcium in a mouse model of ADH1 that use the same sorts of mutations that are found in human beings with this disorder. What you can see at the bottom is that encaleret also serum calcium in clinical trials in patients with osteoporosis, an indication for which the drug failed to increase bone mineral density. So our first study in this program is a Phase II open-label dose-ranging study in patients with ADH1 to evaluate the safety, tolerability and efficacy of encaleret in normalizing serum calcium and urinary calcium. We're planning to study up to 16 ADH1 patients at the NIH clinical center, with a -- with 3 periods of inpatient treatment and 1 period of outpatient treatment with respect to dose escalation and evaluation of the ability of encaleret to achieve its therapeutic goals. So the primary endpoints, again, this is a Phase II exploratory study. So safety and tolerability is paramount and is our top objective for the study as well as to measure blood calcium, urinary calcium, PTH concentration and bone turnover markers in terms of additional measures of efficacy and overall safety. So we expect top line proof-of-concept results from this study in early to mid-2021. I'd now like to introduce Dr. Michael Collins, who's the chief of the Skeletal Disorders and Mineral Homeostasis section at the National Institutes of Health in Bethesda, Maryland. Mike's research focused on the roles of PTH and FGF23 in bone biology and mineral homeostasis over a very storied career with lots of top line publications. He's the corresponding author on the publications of calcium-sensing receptor antagonist in the context of ADH1 and is both our clinical adviser and key collaborator in this project. Mike, I'd like to turn it over to you now to make some additional comments about this exciting project.

Good morning, everyone. I'm thrilled today to be here to talk to you about encalaret for autosomal dominant hypocalcemia type 1. It's exciting public-private partnership between the National Institutes of Health and BridgeBio. The way I'm going to approach this today, I'll give you a bit about calcium regulation, calcium-sensing receptor and calcium-sensing receptor diseases, autosomal dominant hypocalcemia type 1 and the diseases and the patients, a bit about the calcium-sensing receptor antagonists and specifically, how we'll use them to treat ADH-1. But first, why is calcium so important? Probably needless to say, it's important in cell signaling and neurotransmission as a co factor for enzymatic reactions involved in many macromolecules. Importantly, it's critical to the maintenance and the formation of the skeleton, which we use for locomotion and protection, which also serves as a reservoir of approximately a kilogram of calcium. On the right panel here, you can see blood calcium levels over a 48-hour period. And you'll notice relative to example to phosphate that blood calcium is maintained rigorously within a very narrow range over the course of the day. You'll see that the wide excursions that take place, for example, in parathyroid hormone and FGF23, which are involved, to some extent, in the regulation of calcium vary quite a bit throughout the day, the goal being to maintain calcium in this very narrow range. Blood calcium is essentially maintained by 4 organs, parathyroid gland, the kidney, the bone and the gut. The parathyroid gland and parathyroid hormone are the master regulators of calcium. Parathyroid hormone acts at the kidney to promote reabsorption of calcium from the urine, the purpose of which is to maintain blood calcium. Parathyroid hormone is always about maintaining blood calcium. Parathyroid hormone also stimulates the formation of the active potent 125D from the kidney, which acts at the gut to promote the absorption of calcium, which again raises blood calcium. Parathyroid hormone also acts on the bone, to stimulate the resorption of bone and the release of calcium from the bone, again, to maintain blood calcium. Far and away, the master regulator of all this process is the calcium-sensing receptor, sometimes referred to as the calciostat. It's shown here in the left panel. It's a G protein-coupled receptor. It has a very large extracellular domain. It's a homodimer, and it binds approximately, probably 4 molecules of calcium, ionized calcium. Calcium-sensing receptor was discovered in 1993 by both Ed Nemeth and Ed Brown. Shown in the next panel is a very important aspect related to the calcium-sensing receptor and its physiologic function. And this is the dose relationship curve between extracellular calcium and parathyroid hormone secretion. And as you can see, it's a very steep dose response curve where there's huge changes in parathyroid hormone release with very small changes in ionized calcium. And this is the key feature about the regulation of blood calcium by the calcium-sensing receptor, both in the parathyroid gland and in the kidneys as we'll see. It's this property of the calcium-sensing receptor that allows it to maintain blood calcium in this very narrow range that we saw on this earlier slide. There's primarily 2 tissues that are involved in the regulation of blood calcium via the calcium-sensing receptor. And the first is the parathyroid chief cell, which is shown here, and it's involved in responding to extracellular calcium with the secretion of parathyroid hormone. The other and very important regulator of blood calcium is shown here, and this is in the kidney, the renal tubule cell. The calcium-sensing receptor is expressed all along the nephron in various places, the proximal convoluted tubule, the thick ascending limb and the distal convoluted tubule. As expressed in sometimes in the apical or urine side of the tube and sometimes in the basolateral or blood side of the tube. And this allows the calcium-sensing receptor to have exquisite control over the reabsorption of calcium in the urine. Calcium is all filtered at the glomerulus and reabsorbed along the tubule and the kidney is the last stop before calcium goes out into the urine. This is critical for the regulation of calcium. This is a critical location for the action of calcimimetics and calcilytics. So what are the diseases of the calcium sensing receptor? One is familial hypocalciuric hypercalcemia. This is caused by loss of function mutations in the calcium sensing receptor variant. In this mutation, the calcium sensing receptor thinks that blood calcium is low and the dose response curve has shifted to the right, as you can see here. In this condition, you have increased parathyroid hormone, increased blood calcium and a relatively lower urine calcium. And we have this underlined because this will become important later, and we'll talk about that near the end of the talk. The disease that we're focused on today is autosomal dominant hypocalcemia type 1. And this is gain-of-function mutations in the calcium sensing receptor variant. And in this case, the calcium sensing receptor thinks that blood calcium is high. The dose response further shifted to the left. We have low PTH, low blood calcium and relatively high urine calcium. And this is one of the biggest problems in this disease is the high urine calcium. So I want to give you a flavor of what this is like by describing a patient who we have taken care of here with ADH1 at the NIH for a long time. So he's 51 now. We've seen him for 13 years. He was diagnosed when he was 6 years old when he was noted to have learning difficulties and difficulty concentrating and was found to have low blood calcium. This is one of the features of hypocalcemia is this sort of fogginess that patients describe. From the ages of 6 to 28, he was treated with conventional therapy, which includes calcium and CASA trial, which is a form of 125D. Throughout his life, he's had frequent camping, paresthesias and occasionally this fogginess. Shown here are some complications that we've had, and this is nephrocalcinosis. You can see that white in the kidneys is calcification of the kidneys, which is obviously a bad thing and can lead to renal dysfunction and even renal failure. Also noted in the lower panel is calcification of the basal ganglia of the brain. This is quite a common feature. We're not quite sure exactly how this occurs, and it's not completely clear if this has really any clinical sequela. But very interesting is the family history of this patient. So not unlike a lot of families like this, the father was diagnosed with the same condition when the boy was diagnosed. They checked him. He was also hypocalcemic and eventually a diagnosis with ADH1 was made. But what is most striking about this patient, and I'll never forget this, and this was really -- had an impact on me was the fact that this patient had 2 siblings, 1 older, 1 younger, who had died before the diagnosis was made, and then both died in the neonatal period accompanied by seizures. Certainly, this was probably related to their ADH1. So this reflects how bad this disease can be. It reflects the spectrum of the disease. The father had gone through most of his life without even knowing he had this. This patient fits along pretty well, not too bad, but he does have complications. He's only 51, and he's got this very significant nephrocalcinosis and already has stage 3 chronic kidney disease. So the -- one of the big problems with hypoparathyroid is and especially with ADH1 is where they have a double whammy. They not only have loss of PTH action at the kidney, they also have a loss of the calcium sensing receptor in fact at the kidney. And what happens is what you can see here is when patients begin treatment for their hypocalcemia with hypoparathyroidism, and as you begin to raise the calcium into the normal range, indicated here, you can develop hypercalciuria, and this is what contributes to the nephrocalcinosis and renal problems that you see in this pictures. So this really very much is a disease where you're walking a tight growth in treatment. You want to keep the blood calcium up, but if you keep the blood calcium up too much, you raise the urinary calcium and lead to nephrocalcinosis. And this is particularly difficult in ADH1, and we need a better treatment for this. So what is a better treatment? A better treatment we think is calcilytics. What are Calcilytics? So calcilytics and calcimimetics are agonists and antagonists of the calcium sensory receptor. As I said, this calcium sensory receptor was discovered in 1993 by Ed Nemeth when at Brown. By 1996, Ed Nemeth and other scientists at NPS Pharmaceuticals had discovered the first calcimimetic, an agonist of the calcium sensory receptor. They then described a few years later, antagonists of the calcium sensory receptor, calcilytics, which will be what we're going to talk about later. But this is how they work. So calcimimetics shift the dose response curve in patients with FHH for hypoparathyroidism back to their normal range. In ADH1, calcilytics shift the dose response curve to the right, restoring the normal relationship between blood calcium and parathyroid hormone secretion, for example. So this is when I first got involved in this field was with the use of a calcimimetic. And this was a patient that I saw at the clinical center where I was a trainee. I was an endocrine fellow here. And we admitted a patient in 1996, a 78-year-old man with wildly metastatic parathyroid cancer. He was obtunded, unresponsive to conventional therapy. There was really nothing for this man to do. So I had heard about NPS R-568 from a colleague here. What did you do in 1996? I dialed 411 and got the phone number for NPS Pharmaceuticals in Salt Lake City, Utah. I talked to Ed Fox and Ed Nemeth and we were -- told them I was interested in getting this compound for this patient on a compassionate use basis. They said sure. Things were easier back then. Within 2 weeks, we had an agreement, and we were treating this patient with NPS R-568. And the response is shown here, and it's really dramatic. He had an immediate response to the drug. We increased the dose of that and you can see quite clearly that this restored his blood calcium to a tolerable range for him. He returned to work in New York City. He was effectively treated for 4 years. And quite tragically, he was struck by a car and died from complications due to that car accident. Nonetheless, this told us that agonist of the calcium receptor could work. So what was next? NPS licensed calcimetrics to Amgen. They went on to develop cinacalcet Sensipar, and it's become approved for secondary hyperparathyroidism in 2004 and parathyroid cancer in 2001. What about calcilytics for ADH1? Here's a brief history and a bright future. So calcilytics really do represent precision medicine for ADH1. Calcilytics have increased PTH, which was thought initially that it might be a good treatment for osteoporosis, like the drug [indiscernible]. So this is where calcilytics got hung up for a long time. 1993, NPS licensed calcilytics to GSK for osteoporosis. They eventually developed their lead compound, ronacaleret, and it failed in clinical trials as did all the other calcilytics developed by several other pharmaceutical companies. Along the way, 2007, we had negotiated with GSK to start a proof-of-concept study for ronacaleret in ADH1. As I said, the drug failed in 2008. That program was abandoned, and GSK abandoned calcilytics for bone and mineral disorders. So that was a sad day for us. But 2011, NPS Pharmaceuticals licensed NPS 795 back from GSK, and we started a study for ADH1, a proof-of-concept study here at the NIH. And the results of that are shown here. Primary endpoint in this study was percent change in PTH, which we were able to achieve. You can see the design here was a 3-day study. 3 different IV infusions, a bolus and then a sustained injection on the other 2 days. And while you can see there was a robust change in parathyroid hormone in terms of percent change, the actual changes in the lower panels in PTH were quite modest, and the result of this modest change was that there was really no effect on blood calcium. However, as you can see in the lower panels, there was a decrease with the higher exposure in the fractional excretion of calcium, which reflects the sort of the thing that you want to see at the kidney when you give a calcium load. This will help restore blood calcium. So with that, we were eager to continue. 2015, however, Shire Pharmaceutical acquires NPS. Everybody that was on the calcilytics teams leave Shire and interest is lost. 2019, Shire is acquired by Takeda, even less interest. So it looks like calcilytics was dead for a while. That brought us to 2018, and BridgeBio came and visit us here at the at the NIH in regard to a study with infigratinib that they had acquired from Novartis that you had learned about earlier today. Part of that acquisition included a study that we were doing in tumor-induced osteomalacia, which I'm pleased to say you can read about. It was published 2 weeks ago in the New England Journal. Anyway, at that time, I suggested to Michael Henderson, the possibility that calcilytics might be something that BridgeBio might want to pursue. They left. I fully expected not to hear from them again about this, but lo and behold, Michael came to the rescue. We started this study that you have heard about, Jonathan described earlier. And in fact, the first patients were dosed yesterday. We've already lined up or recruited 9 of the 16 patients. Things look really good. Now we're really excited about this. So the last thing I want to say, though, is this that this, I think there's also a future beyond ADH1. In postsurgical hypoparathyroidism, I think we'll be able to decrease urinary calcium in a way that none of the other drugs out there can. And very interestingly, in a larger market, idiopathic hypercalciuria, I think that we'll be able to convert these patients to an FHH-like phenotype. Remember I told you earlier that it will reduce urinary calcium. So with that, I'll close, and acknowledge some of my key team members here. First of all, I'd like to acknowledge Rachel Gatlin. She's the best partner in research anyone could ever have. She and I have worked together for 20 years, and she has really been the force behind taking this project forward. I'd also like to acknowledge Ed Nemeth. He and I have been at this for a long time now, and it's very gratifying for us that this trial is proceeding. Also, I'd like to acknowledge Karen Pozo, who's the research nurse of the study. She's done a tremendous job. There's been a lot to do, and she's been great. The rest of my team shown here, especially Beth Brillante who is -- I've worked with for a long time, and she's the director in the clinical director's office for clinical operations. Two other physicians on the study, Irish Hartley and Kelly Roszko. Of course, the Calcilytix team, Michael Henderson, Eric Gomes, who was the one who did the due diligence on calcilytics; Jonathan Fox, the medical lead on this; Ramei Sani-Grosso, who has been a pleasure to work with; Anand Lenny; and the newest addition, Dexter Kennedy. Last but not least, I'd like to acknowledge Steve Marks, who was my mentor at the time and helped us get the NPS R-568 study going, which was the basis of why I'm here today. And with that, I'll close and take questions.

Great. Thank you, Dr. Collins. We're now going to transition to talking about the target oncology program within BridgeBio. I'd like to introduce Eli Wallace. Eli is the Chief Scientific Officer in residents for BridgeBio Oncology. He is a leading medicinal chemist who was previously Chief Scientific Officer at Peloton Therapeutics and Director at Array. He has led multiple research projects contributing to 3 approved drugs and 13 INDs.

Good afternoon. I'm Eli Wallace, the Chief Scientific Officer in charge of oncology research at BridgeBio. Today, I'm going to give you a brief overview of our research oncology portfolio and introduce my colleague, Professor Frank McCormick. Before I do that, let me tell you a little bit about myself and why I joined BridgeBio. I joined BridgeBio in December of 2019. And immediately, before that, I was Chief Scientific Officer and one of the original employees at Peloton Therapeutics. At Peloton Therapeutics, we discovered and developed the first-in-class HIF-2alpha inhibitors, which were previously believed to be an undruggable target. Those have shown excellent activity in both the metastatic kidney cancer as well as in VHL hereditary cancer syndrome. And subsequently, our company was purchased by Merck Pharmaceuticals. Prior to my experience at Peloton Therapeutics, I was a Director of Medicinal Chemistry at Array Biopharma for over 10 years, where I led many of their oncology research programs, including 3 programs that have led to recent approvals, including binimetinib for melanoma, selumetinib for NF1 and tucatinib for breast cancer. Joining me on our senior oncology research teams are Dr. Pedro Beltran, who has over 20 years experience in cancer research, drug discovery and development; obviously, Professor Frank McCormick; and Dr. Richard Scheller, who is our Chairman of R&D. Now I'd like to spend just a minute on you why I joined BridgeBio, and that's really because I wanted to continue to work on novel challenging oncology targets. I wanted to work in an environment that was collaborative with leading academic centers. And I also wanted to continue to work in a small biotech environment where we had autonomy, flexibility and focus to really drive our progress forward in a model that has proven very successful in my career. And BridgeBio allows me to do that in an environment and which is part of a larger organization. So I get both the advantages of the small biotech, but with the important backing and resources of BridgeBio more broadly, which includes, obviously, scientific expertise, but also with the resources needed to execute on our programs. Now I'd like to give you a brief overview of our research oncology portfolio, and that starts with -- HIF -- excuse me, starts with SHP2. SHP2 is an optogenetic phosphatase that drives cell growth proliferation through the activation of the map kinase pathway, and it also plays a very important role in immunosuppression through T cell exhaustion. On this program, we have developed -- or discovered and developed BBP-398, a novel SHP2 inhibitor that we have optimized for both safety, pharmacokinetic and pharmakinetic profile -- pharmacodynamic profile, excuse me, that we believe will optimize both monotherapy potential of this class of inhibitors as well, importantly, combination therapy. The IND has cleared for this molecule, and it should enter the clinic this quarter. Our next set of targets are, of course, KRAS. We attack KRAS from multiple different angles, and I'll talk a little bit more about this in subsequent slides, and this will also be the focus of Professor McCormick's remarks. And our third class of targets is GPX4. This target exploits a recently discovered new cell death mechanism, Ferroptosis. Ferroptosis results when oxidized peroxide radicals accumulate in the cell membrane, leading to cell death. And this is avoided in cancer cells through the activity of glutathione peroxidase 4, GPX4. GPX4 acts to detoxify these peroxide radicals, allowing cancer cells to avoid this cell death and survive and continue to proliferate. We inhibit GPX4 with oral inhibitors and that we are well positioned to move forward with a first-in-class oral inhibitor of GPX4. As I think is well-known by this audience, our RAS efforts are part of a collaboration that allows us really to move forward on many fronts to tackle this challenging target. We have a collaboration in parallel with Frederick National Labs and the NTI RAS Initiative, where 60 of the world-class scientists focus only on RAS biology. And this allows us access to cutting-edge technologies, including world-class structural biology. And we also have a collaboration with Lawrence Livermore National Lab, which allows us access to the world's third fastest computing system where we can use that to do computational modeling and importantly, frequently get important molecular dynamics simulations that help us drive our programs forward against KRAS. An example of the collaboration, I'll show just briefly, and this illustrates the power of molecular dynamics. Here, I show one of our projects where we're attacking C185. This is an important target in the hypervariable region of KRAS4b. This region is required for KRAS4b to translocate to the membrane and for activity. And so the hypothesis is if you can attack this region that you can inhibit its membrane translocation and its activity. Here, you see a crystal structure that shows you a static picture of the protein with the hypervalent hypervariable region in blue and interacting a little bit with the G domain, and you do get some insights from the static picture. But when you compare that to the insights that you get from molecular dynamics, shown here in this movie, you can see how variable that -- and how much movement is in that blue region and how many different interactions it makes with the G domain. And the ability to see this in live action allows our team to see many more potential sites where we can drug this target and really moves our progress forward. So one last slide before I hand it over to Professor McCormick. We tackle KRAS by multiple different approaches and all of these approaches are pan-mutant approaches. Each has a unique mechanism of action, each with a novel pocket that we target. Our first program that targets H95, a novel resident -- or a unique residue, I should say, within KRAS, it's not present in H or NRAS. And when we combine to this residue, we can target all of KRAS, whether there's mutants presence or not. Our second program is a very novel approach that tackles the effector interactions between PI3K and RAS, and so we can block that interaction. Again, agnostic to the type of mutations that KRAS may have present. And our third, as I just mentioned, is targeting C185 to target KRAS4b's localization to the membrane. All of these programs are part of the collaboration, as I mentioned, with the RAS initiative, and Lawrence Livermore National Laboratories that allow us to have a competitive advantage, both from structural biology and biophysics, but also, as I mentioned, molecular dynamics. And then the third leg of that is that we bring forward a powerful oncology research discovery team that includes some scientists that have worked with me for years, both at Array Biopharma, where we had a lot of success; at Peloton Therapeutics; and also from other organizations such as Amgen and others. So the last thing that remains for me to do is to introduce my friend and colleague, Professor Frank McCormick. He is a co-founder of BridgeBio and our Chairman of Oncology. Currently a professor at UC San Francisco. A founder of Onyx Pharmaceuticals where they made contributions to the oncology drug discovery and development space through sorafenib and palbociclib. And Frank is a if not the world-leading expert in RAS biology, and he's going to tell you a little bit more about some of our RAS program.

Thank you, Eli. I'd like to spend the next 10 minutes explaining to you why RAS proteins are such important clinical targets and why they've been so difficult to target with small molecule drugs. And then I'll finish off with a very brief summary of 2 of the approaches that we are using to nail this major clinical problem. In this slide, I'll show you the frequency of RAS mutations in human cancers. And you can see that KRAS is very frequently mutated in pancreas cancer, colorectal cancer and in lung cancer. Other members of the RAS family play important roles in other diseases, such as AML, melanoma, bladder cancer and thyroid cancer. But KRAS is really the major clinical problem that we need to address. In these particular cancers, the KRAS mutation is actually the major driver of the cancer. That is every cell in the tumor contains a mutant protein and depends on the mutant protein for its survival. This is being validated by many different approaches and really tells us that KRAS is really ideal target if we can find ways of targeting the protein effectively. And that is the real challenge that we need to face. The mutations which activate the KRAS protein in pancreas cancer called G12D and G12V most frequently; similarly in colorectal cancer, G12D and G12V. And in lung cancer, G12C is a more frequent mutation. And that's because G12C is the result of exposure to tobacco smoke so that's rather special to lung adenocarcinoma. So we're ready to find drugs that hit KRAS and specifically G12D, B, C and the other minor variants as well. Now there are multiple challenges in targeting KRAS. These relate to the complexity of signaling and the redundancy of the RAS proteins themselves. The left wiring diagram, which you won't be able to see in detail, is just -- makes a point that RAS protein is in a circle there are class of a very complicated signaling network. We send signals from all growth factor receptors into the cell to tell them to divide. So all cells depend on RAS proteins for their separation and their survival. This point -- this slide also makes a point that as the network is very complicated, so far, it's been impossible to shut down this network by intervening with small molecule drugs that target downstream kinases and other related proteins such as MEC and ERK. These are druggable targets, and there are great drugs that are being developed, including by Eli. But when these drugs are applied to RAS cancers, they have not been effective because of the complexity of the signaling network. On the right-hand side, just to make the point that RAS proteins are partner with very large superfamily of proteins, each of which is a binary switch which controls some very specific biological process in the cell. So these switches control every aspect of cell biology. And it's important that when we find drugs that target one particular part of this network, the KRAS protein in this case, we don't interfere with all the other switches that are necessary for normal cell function and survival. So it's very difficult to find drugs that are selective enough and accommodate this redundancy. But from a technical point of view, the KRAS protein presents a very difficult target. It's been described as a squishy tennis ball in which the surface of the protein is kind of malleable and switches back and forth from the active state to the inactivate state. Let's run this animation again. We see protein switching back and forth from the 2 states. But the surface of the protein does not have any deep pockets in which a small molecule can easily bind. So it's been naturally perhaps impossible to find small molecules that bind to this protein with very high affinity. Therefore, covalent approaches seem like the better approach, and I'll describe 2 covalent approaches that we are employing to target KRAS here in just a moment. Now RAS protein's function in plasma membrane. Each of these green dots is actually a RAS protein jiggling around in the plasma membrane. And it functions by recruiting other proteins to the plasma membrane, such as the red dots, which are RAF kinase. We know a lot about how the protein inserts in the membrane and how it functions in the membrane. But one of our major therapeutic goals is to get the protein off the membrane where it needs to be to function. So preventing RAS localizing in a membrane prevents it in gating with other proteins and then turns off the proteins by biological activity. And that's the basis of our first approach to having KRAS. So here we see a simulation of a RAS protein bobbing around in the plasma membrane. The squishy tennis ball is held into the plasma membrane by a floppy tail, and that is acted in the membrane by a lipid group at the C-terminus called the farnesyl group or a general group. There's a stick diagram on the right that shows the tennis ball on the left of this ball here. And then the stick is the floppy tail. And the red sea there is assisting to which farnesyl or general groups are modified to localize the protein the plasma membrane. So our first approach is to find compounds which covalently attack that system and therefore, prevent modification of KRAS by other farnesyl transferase or general journal transferase. And the compound is expected to bind somewhere on the surface of the squishy tennis ball and then covalently hit the system as the floppy tail flops around. This simulation shows that in flat at the tail of the KRAS protein does actually sample space and eventually finds a place on the G domain where it can sit down, and that is the pocket to which our compounds bind. So our small molecules, as shown in the right panel here, bind into a little groove in the KRAS protein. And then the yellow blob, on the top left, is Systane from -- at the end of the C-terminus tail. When this flops over into the G domain, the tennis ball part of the protein, we see covalent at the top on the Systane, which irreversibly blocks the C-terminus of the KRAS protein and prevents farnesylation or general generalation and therefore, prevents the RAS protein accumulating in the plasma membrane and fuels its biological activity. Now there's some data here that show that, indeed, in a dose dependent manner, one of our compounds, prevents KRAS localization in a plasma membrane, as shown in the left-hand panel, by Western blot analysis. On the right-hand panel, we see on-target effects in the blue line and off-target effects as a control in the orange line. So we do have compounds that act in cell to prevent KRAS processing and shut down KRAS processing as a result of farnesyl localized in the plasma on brand. So that's the basis of our first approach, preventing newly synthesised KRAS from getting farnesylated and processed and therefore, keeping it in the inactive state. Now as we were looking for our compounds to take this approach forward. We identified a tool compound we call FB9, which itself is not a drug candidate because it's too reactive, but it showed us a very interesting property, which has been the basis now of our second major projects in this area. Now this compound has the remarkable property of getting into cells and destroying KRAS specifically without affecting other RAS proteins, like HRAS and NRAS. So you can see here, the exposure to this compound in a pancreatic cancer cell line destroys KRAS protein. Now this drug is not working by preventing newly synthesised KRAS coming to the membrane. Instead, it hits the fully processed mature protein. And first, I could not understand how this was working. But through our collaboration with our colleagues at the Federic National Lab, we were able to figure out that this compound actually reacts with a histidine in the RAS protein, not assisting as we'd originally anticipated. Now this we found extremely interesting because the histidine residue, which this compound targets, is actually unique to KRAS. So on the bottom of this slide, you will see a series of amino acid sequences of the H, N and KRAS proteins. And you can see in red highlighted in histidine, which is unique to KRAS amongst all the superfamily of RAS proteins. And so this histidine is actually amenable to attack by covalence inhibitor. There are actually 3 drugs approved which hit histidines covalently, which gives us encouragement that we can do the same thing for targeting histidine in KRAS. The histidine is shown down in the middle of the protein now sticking up on edge of the Helix. It's right by the switch to pockets where the G12C compounds that have been developed by Amgen and Mirati and Janssen and Genentech. Their compounds bind in that pocket, but their compounds only binds to the inactive form of the RAS protein. This histidine is available in the active form of the RAS protein and is available in all the different mutants of RAS protein that cause human cancer. So we believe that if we can find a safe version of the compound that I showed you earlier on that has correct drug like properties, this drug could shut down all the mutant forms of KRAS and do so by hitting the active form of the protein, which is by far the preferable approach. So this is our major focus right now because of the potential, obviously, the enormous upside of targeting this particular amino acid with this approach. So through a combination of medicinal chemistry and structural biology and computational analysis through our wonderful collaboration with our colleagues at the Lawrence Livermore National Lab. We have access to the best supercomputers, structural analysis of the proteins, NMR analysis through our collaborations with Frederic National Lab, all under the guidance of Eli to help bring these ideas through into preclinical compounds, which we hope will advance into the clinic and have a major impact on patients suffering from KRAS tumors.

All right. Thank you, Craig. We'd now like to transition to the Q&A part of our discussion today. I'd like to invite back all of our speakers to have a discussion with us. Just as a note, unfortunately, Ravi is not able to join us due to some timezone issues, but we have all of our speakers here today.

[Operator Instructions] So we're going to get started with one broad question, and then we're just going to really dive into some of the detailed questions on the programs. The first question today comes from Eun Yang at Jefferies. The question is for Neil Kumar. One question. So with 20 programs under development, how do you prioritize them? And what has been the attrition rate from preclinical to clinic?

Yes. Great. Well, let me again thank all of our speakers, learned a great deal, and everyone who's taken the time to dial in this morning. I'll be brief because I'm keen to learn from our terrific team and our terrific collaborators. It's a great question. Actually, we don't think about prioritization from a portfolio standpoint. There's 2 different ways one can do a collection of projects. One is from the portfolio view where you set some sort of a boundary condition, typically it's financial, and then you rank stack programs and you say which ones you really want to focus on versus not. That tends not to be true in a decentralized model like we set up where you take more of a program lens. And as long as the program is meeting specific, go, no goes, and continues to be valid in terms of the therapeutic hypothesis and the science being strong, one continues to progress it. So we haven't really hit the stage yet where we need to artificially prioritize programs. Certainly, if the science doesn't live up to what we had articulated when we brought the program in, we'll shut it down. And I guess to the second part of your question, which is what our historical POTS has been. Preclinically, our historical POTS has been around 83%. It's something we measure quite closely, although I will say that, yes, I expect that we're going to get a better denominator over time. So I wouldn't necessarily say that it's going to be our steady-state average. It's 1 of 3 parameters we look at globally to judge our performance. When we look at POTS, we look at dollars to IND, which obviously is a reasonable marker of our efficiency. And we look at a number of new programs. Are we doing a great job of continuing to source innovation and working with great investigators to turn their insights into medicines that matter. So those are the 3 parameters we look at, and the POTS being one key one there.

Thank you. So let's start with some of the new program questions here. The next question comes from Tyler Van Buren with Piper Sandler, and his question is for Julian Gillmore. How has the diagnosis rates and technicians getting increase with the tafamidis launch so far? What fraction of the true population of this disease do you believe is currently diagnosed today? And how do you expect this to evolve over time?

So thank you very much for inviting me to speak earlier, and thanks for the question. So in terms of the diagnosis rates, in fact, in the U.K., certainly, and I suspect this is true worldwide, the rates started to increase pretty dramatically before the tafamidis launch or there was a great awareness of tafamidis for ATTR cardiomyopathy. And I think that was largely down to cardiac MRI scanning, certainly in the U.K. And then subsequently down to increasing use of bone scans. Since tafamidis and since the results of the ATTR-ACT study were published and since the tafamidis launch, there's no doubt that cardiologists have taken a greater -- become increasingly aware of cardiac ATTR amyloidosis. And I think that that's continued to increase quite dramatically in terms of -- that's resulted in an ongoing increase in terms of number of diagnosis, but I think the awareness had actually started beforehand. Having said that, in answer to your second part -- the second part of the question, I still think it's probably quite a small proportion of patients who actually have this disease who are being diagnosed. Certainly, the wild-type patients, I suspect it's quite a small proportion. It's undoubtedly increasing, but there's a lot of work to do. I mean if we imagine from the data we have in that Spanish study that 4% of patients with -- over the age of 75 with HFpEF have grade 2 or 3 DPD scans, that's potentially a lot of patients with cardiac ATTR amyloidosis, the vast majority of whom are still not being diagnosed. To put a number on it is very difficult. I think it's obviously increasing, and I suspect it's low, the percentage that are diagnosed. But I don't know what the number is at the moment.

Thank you. The next question is for Jonathan Fox, again, on ATTR program. Can you comment on the status of enrollment of the study? And what is the impact of tafamidis availability?

It's Jonathan here. So I'm happy to report that we have closed further enrollment in the study. There are still a number of people in screening. We anticipate most of those people will successfully randomize once they've completed the screening process. We've updated our clinicaltrials.gov posting of the study to reflect this. And in terms of the impact of tafamidis, obviously, since it's launched in the United States, it has presented some challenges to enrollment in the U.S. But outside of the United States, there's been variable market uptake as the manufacturer has negotiated various reimbursement arrangements with national health systems.

Thank you. The next question is for you, again, Jonathan, from Salim Syed at Mizuho. Everything we have seen has shown acoramadis to be a better TTR stabilizer than Pfizer's tafamidis. What are the expectations of -- on the 6-minute walk test data as we head into the readout?

Well, I'd refer you back to the slide I showed as part of my presentation on the natural history of the disease in terms of a steady decline in the ability of people with ATTR cardiomyopathy to perform the 6-minute walk test compared to age-matched controls. What we've seen in the ATTR-ACT data is a very encouraging signal of a slowing of that decline that was apparent even by the 12-month time point in that study according to the publication in The New England Journal back in 2018, and that was what inspired us to create this embedded design of the ATTRibute study with respect to a 12-month readout on 6-minute walk. We powered the study to anticipate a result that would be at least as good as tafamidis. But again, given the quite marked difference that we have published on with respect to the degree of stabilization of the target protein, we anticipate that the performance of the participants in the trial on acoramadis we think is going to be better than the results that you saw with tafamidis.

Yes. Just to put a -- I think that's very well said, Jonathan. We consider the ATTR-ACT data, the declination on tafamidis of these patients of around 26 meters by 30 months and a slowing of the progression of around 50%. We're really looking at that 50% and hoping to do better, as Jonathan pointed out, in terms of that percent slowing in progression.

Sure. I think the next question, again, is from Salim for you, Jonathan. If you have your full TTR stabilization, mechanistically is there a place in the market for TTR knockdown therapeutics?

Yes. That's -- so it's a really interesting question to ponder because if you can fully stabilize the protein, there doesn't seem to be much residual reason to knock it down. It's -- the companies that are taking the knockdown approach are all targeting a substantial but not a complete knockdown, around 80%. So since we don't know all the roles of TTR in human biology, nor the long-term effect of removing it, our principle of targeted disease at its source being the destabilization that is the result of the pathogenic mutations that drive the hereditary form of the disease and whatever the age-related processes that lead to destabilization of the wild-type protein and the wild-type form of the disease. We see complete stabilization as perhaps a more biologically attractive approach. But of course, the data will tell us when we have the readout from the studies.

Great. Thank you. Our next question actually transitions to the achondroplasia program, and this is a question from Mani at Leerink. This is for Susan. Could you please comment on the enrollment of the PROPEL 2 study? And are there any restrictions or stratification by FGFR3 genotype in the study and to what extent is genotype variation a contributor to variability in the natural history for achondroplasia?

Thanks, Christine. So good question. Yes, COVID has caused some delays, but enrollment actually is going quite well in the PROPEL and PROPEL 2 study. The delays were mainly in the March-April time frame. But recently, the impact has been much less and enrollment has picked up, and we are really encouraged by the enrollment rates that we're seeing. And as we mentioned, we've dosed the first patient in PROPEL 2. 95% of the patients will have the same point mutation. And the children need to have a documented FGFR3 mutation. So we don't expect there to be a variety in the genetics of these children.

Great. Thank you. So the next question again is for you, Susan, from Eun Yang at Jefferies. Could you please comment how the molecule is different from the CNP analogs?

Sure. So first of all, infigratinib is an FGFR1 through 3 inhibitor. So it directly inhibits the FGFR3 gain of function mutation, which causes achondroplasia. And in doing so, it inhibits both pathways downstream of FGFR3 to STAT1 and MAPK. And because of the ability to inhibit both pathways instead of only one, we believe infigratinib could have a stronger effect on not only short stature, but the other important health symptoms, the spinal changes, the cranial changes and the symptoms that are really important. And then, of course, we think it's really important that we offer an oral option rather than a daily or a weekly injection, and we think that this could be a meaningful advantage for parents and for children.

Okay. Thank you. And then the next question comes from Salim, also for you, Susan. What would be considered a clinically meaningful improvement in annualized growth velocity, especially relative to what vosoritide has demonstrated?

Right. So vosoritide, I think everyone probably has seen recently publish, the results of their Phase III study. And they demonstrated an effect of 1.6 centimeters per year over placebo, and they've had a durable effect seen in their earlier studies. And we believe that any increase in AGV above that would be beneficial. And based on the preclinical data, we are encouraged and believe that we will see at least -- and hope that we'll see at least that effect on AGV.