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 and D that animates us here at BridgeBio, but it's really only important in as much as it helps us to serve patients with genetic disease. Elliot, 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, our NDA for that disease.
And my hope is with your support and through repeated application of our R and D engine over the course of the coming years that Elliott is the first of 100 of 1000 of potentially millions of patients that we can help together. The second piece of context actually relates to that number, 100 of 1000 or 1,000,000. 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 1 in the era of genetic continue to come up with new ideas as well as to progress our existing ideas toward 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. Number 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 fits 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 aberrant to protein aberrant to molecular pathophysiology to symptomatology. And often it will serve as a 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're the things that make a difference for investors.
And we're going to talk about products at length today. We've got 4 exciting products that will have catalysts over the next 12 months to 24 months in big $750,000,000 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 the products we've created that you'll want to partner with us not only on existing product pipeline, but also on the new ideas to come as we try to scale into this opportunity within genetic medicine that's founded and 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 100 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 cost and increasing quality of exome and genome sequencing and availability of longitudinal databases that allow us to understand a 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 dimensionalize 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 in aggregate, they're quite common. The second way to think about it is the impact of these diseases when one does unfortunately acquire a condition. And this is the 2nd 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 the 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 1,000 pages. I'll save you the reading.
It's by Lawrence Freeman. It's a beautiful book. 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 1, they establish the correct playing field.
Number 2, they establish simple tenants that everyone can abide by. And number 3, 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 tried to do was to learn from these principles and say, we're going to place ourselves in the right playing field, that's genetic disease.
You look backwards in time, probability and 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 had started would be the right one, but we're going to put ourselves on that playing field. Number 2, we're going to opportunistically evaluate all of the opportunities that we see based on 2 very simple tenants. Number 1, is the science beautiful?
Can we effectively connect the dots from genetic aberrant 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 hype bubble and 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 we're not going to use a 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 there lies innovation that's lying fallow 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 book. 2 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 of 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 go super linearly tend to be decentralized versus centralized.
So what do we do? Number 1, we establish simple rules that apply anywhere within the context of BridgeBio. It doesn't matter if you're working at 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 vary 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 and D.
So we have small teams that focus at 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 sub linearly 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 1, 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 3 50 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 including 2 key ones actually in LGMD2I, which is a big disease and ADH1, which is one of our key catalyst drivers where we just announced the initiation of our Phase 2 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 at We showed dose dependent increases in collagen 7 against dystrophic epidermolysis bullosa program, a couple of months ago. We've shown preclinical but interesting data in the context of general adrenal hyperplasia and Canavan disease.
In the first case showing that we have a durable both mRNA BGC count and now protein expression in the adrenal cortex. And in the latter case showing that IV ROA is effective, it's now more effective than other ROA alternatives. In achondroplasia, we've continued to present data that suggests that we might be able to have effects for these tiddos 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 the 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 scale and that I think is a product not only a 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 does 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 in R and 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 Humbar and ClinVar, but now we're gained access to the U. K. Database and Finjan, etcetera. And we can do de novo target discovery.
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 loss of 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 geneticists. 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 medallion diseases to say which of those diseases are truly well characterized, where can we go from genetic aberrant to protein aberrant to quantitatively map this thing all the way to symptoms. We have 14 different 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 3rd 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 were co founders of BridgeBio from the get go.
Charles and Frank were 2 co founders. Charles was my mentor at 3rd Rock Ventures. He put together GPT. He and I worked on myocardia together and he's really been a driver and leader in this area of Mendelian and genetic disease. Frank McCormick similarly was on the SAB at Third Rock Ventures, really thinks very about precision oncology, leads our oncology efforts and leads our key RAS and GPX-four efforts that you'll hear about later today, is also just a wonderful mentor and friend.
Richard Scheller, the former Head of R and D at Genentech and at 23andme is our Chairman of R and D, oversees a lot of our target seeking and target evaluation activities and is very deep in the science of both CNS diseases, which are very important in terms of capital insufficient, the next really frontier, I think, in the top 20 or 30 medallion disease markets of size, but also elsewhere has been a remarkable mentor. Len Post, who is the former CFO of Valmarin and Phil Reilly, who I had the pleasure of working with at ThirdRock 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 axioms that are working in the area and ultimately to help us to evaluate the progression of our pipeline. And how does that 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 Eli Wallace, 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 paths 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 buoyed by a set of infrastructure that I think we don't talk about that often, but is interesting, screening infrastructure. We work with the 3rd 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 our small molecule programs are very interesting in the context of gain 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 7 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 wait to see whether or not we're getting true functional improvement with these patients, but a lot to be optimistic with the recent 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 you can expect more to come, obviously replacement of intracellular proteins and loss of function diseases.
And I think importantly working on the 2nd 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 with haploinsufficiency, doing some of the things that people have talked about in terms of up regulating the expression of genes of interest, but I think taking a couple of novel approaches to it and 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 almost 15 INDs now over the 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 Priya, 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 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's 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 in different geographies. This is how you conduct a remote SIB versus an in person SIB, etcetera, etcetera, etcetera.
I think we've got the ability to shave weeks, if not months off of a variety of Phase III clinical trials, which will make us the best owner of these assets as we move in to 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 of 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-nineteen 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 commonalities as well that we can apply.
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 to scale. And then the final piece is the 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 we're given the opportunity to commercialize the big one in TTR and then Aecon and then CAH 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, our CCO, Matt Alton, 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 has been delivering over time. So as I mentioned over 10 INDs, 20 plus disclosed programs, 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 1 if you graph a 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 one of our product programs that are either best in class or 1st in class in some very large opportunity areas. Let me start with a manifestation of all of the product engine activity that's ongoing, which is our pipeline is currently disclosed today.
I'll just make a couple of comments that are interesting as we think about strategy. Number 1, 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 a 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 1st 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 sizes are quite large here and that the upcoming events are seminal. They're either Phase 3 readouts where we will show real effect on feeling better or mortality. And on the flip side, their proof of concept data points that will show effect against what we think to be registrable endpoints for those Phase 3. 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 at 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'll be 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 $1,000,000,000 plus market opportunities. Several of these are on targeted oncology, which does make sense. Some of them are in the rare, there's maybe 20 or 30 medallion diseases according to our market mapping that really will be $1,000,000,000 plus opportunities and we're playing in at least 3 of them.
So that's of interest and I think we continue to play in 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's an 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. Julian, who's 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.
He's helped us tremendously to understand TTR amyloidosis as it relates to cardiomyopathy and the context of the disease mechanism as well as in the context of clinical application. Kiki, who is 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 Pollans, who's I feel like working across at least 4 or 5 bridge file programs. We'll be talking about 1 in ADH1 where we recently announced the onset of our Phase 2 trial. He's 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. Before we begin our program highlights, I'd like to remind the audience that there will be a question and answer session following all of the program highlight sessions. You do need to be logged into the video link in order to submit questions. 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 bridge bio company developing infragratinib 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 and D Day. So QED Therapeutics is developing infragratinib for FGFR driven conditions, including development of very low dose infragratinib for treatment of achondroplasia. Achondroplasia is the most common cause of disproportionate short stature and in fact 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 stature parents. Preclinical data suggests that infobratinib 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 pathways, mapk and stat1, which together result in abnormal growth plate development and can cause the symptoms we see in people with achondroplasia. So, of course, short in 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 the skull through which the spinal canal passes, that can also be tightened and foramen magnum stenosis can lead to neurologic emergencies in children that would require emergency neurosurgery.
In addition, foramen magnum stenosis has been associated with sudden infant death. We believe infragatinib as an orally available FGFR inhibitor has the potential to be the best in class approach by directly inhibiting the overactive FGFR receptor, blocking the upregulated STAT1 and MATK signaling pathways, which would ultimately allow for reversal of the key driver of symptoms. Preclinically, we have evidence of efficacy for infragratinib to positively affect the achondroplasia phenotype. In a validated achondroplasia mouse model, we have seen positive changes in the cranial bones, so an increase in the foramen 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 length of long bones. The mouse studies have also been repeated at lower doses of infragratinib, and we see a robust dose response relationship for infragatinib 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 fizer agent in a slightly different achondroplasia mouse model.
Of course, none of these agents have been compared directly in the same experiment. But we believe infragatinib has the best mechanism of action of the achondroplasia treatments in 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 Professor of Clinical Genetics at Murdoch Children's Research Institute in Melbourne, Australia. He's the Foundation Director of the Southern Cross Bone Dysplasia Center 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 inflogratinib 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 infragratinib in achondroplasia. Ravi?
Hi. It's nice to be here today. I'm sorry I can't be here in person with you for this R and 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 main 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, the partners and 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 a large proportion of individuals who have achondroplasia. And these can be as significant as the 50 times relative risk of sudden infant death like syndrome in the 1st 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 contributes to a high incidence of infant mortality because it compresses the very vital brain structures that go through there, including the respiratory center. And there really have been no consensus on the guidelines and marked 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 increase 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 it'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 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 dysplasia 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 high 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 and teenagers and young adults with achondroplasia who tell me that unfortunately, even though we live in a supposedly politically correct world, teasing and cyberbullying is a reality. They have photos taken of them that are then posted on 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, the way they 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 concentrate on psychosocial well-being. And I guess the psychosocial well-being of our community has really been highlighted by this current COVID-nineteen issue and the fact that psychosocial aspects and the mental health of communities in lockdown is certainly being 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 the permission of one of my patients who's been in one of the trials, 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 a 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 five 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 mean 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-two. 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 story 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 foramen magnum growth and lay down the foundations that will provide better health for these children as they progress through childhood and adolescence and importantly into adulthood as well.
So I think that's extremely important. And then that will lead into the Phase 2 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 2 study, our primary objective is to identify a safe and therapeutic dose for further expansion into further pivotal 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 chain from baseline in Admiral Graz Growth Velocity. And then once those things have been established and a 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 schema of the types of things that will be occurring, already occurring and are due to occur in the next 24 months.
There are 6 countries around the world participating in this 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 that 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 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, Ravi, for that compelling overview of achondroplasia. We're now going to transition to discussing our program for ATTR. I now have the privilege of introducing Jonathan Fox, our Chief Medical Officer for Eidos and Head of Cardio Renal Diseases at BridgeBio. Jonathan was previously the founding Chief Medical Officer at MyoKardia and held senior positions at SmithKlineBeacham, Merck and AstraZeneca. Jonathan?
Thank you very much, Christine, and thank you, ladies and gentlemen, for joining us today in our virtual R and 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, acaramidis 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 Akaramanis, a potential best in class drug that mimics a naturally occurring rescue mutation.
Akaramidus has been well tolerated and demonstrated near complete TTR stabilization in Phase 1 and Phase 2 clinical studies. We're currently executing a Phase 3 study in cardiomyopathy with top line data expected in late 2021 or early 2022. Akaramidus 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 a 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 is 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 dissociates the tetramer dissociates 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 Akaramidus, which was designed to mimic that protective T119M mutation, it stabilizes the tetramers to slow or halt disease progression. As I mentioned, acaraminis has been generally well tolerated and demonstrated near complete TTR stabilization in preclinical Phase 1 and Phase 2 studies. On the left hand side of this slide, we see a safety summary from the Phase 2 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 and 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 in their severity or seriousness. On the right hand side of the slide, we see a representative display of data from 1 of the GTR stabilization assays that we used. And you see that even at trough that is to say the blood level of Akaramidus prior to the next dose at steady state, there was 100% stabilization by that assay. The AATTRIBUTE cardiomyopathy study, which is our Phase 3 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 have had their diagnosis established either by a positive biopsy showing ATTR or through the non invasive diagnostic algorithm that was published in 2016 by Gilmore 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:one 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. ATTRIBUTECM is designed to evaluate the safety and efficacy of Akaramidus across a series of complementary measures of both drug activity and ATTR cardiomyopathy disease progression. We will be measuring TTR stability by the 2 established assays of western blot and fluorescent probe exclusion. We will be analyzing disease biomarkers of serum TTR and terminal probe BNP 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, the SIC 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 is 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 tafamidisattract studies placebo arm and the tafamidisattract active arm.
And so an optimal profile for Akiramidis 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 pairwise 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 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 counted 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 pairwise 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 Akiramidis 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 Centimeters.
We're also launching a program in polyneuropathy, the ATTRIBUET 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 best treat them. I'd now like to introduce Professor Julian Gilmore, who is the Center Head at the University College London Centre For Amyloidosis and Acute Phase Proteins. Professor Gilmore's research interests include the pathogenesis, diagnosis and treatment of amyloidosis. He is the co author of over 250 peer reviewed articles, including numerous regarding ATTR, and he's also the co chair of our Tribute Centimeters steering committee. Professor Gilmore, over to you.
So thank you very much for the introduction. It's a great pleasure to be here this BridgeBio R and D Day. So I'm going to talk to you about the epidemiology and clinical features of transpiratin, otherwise known as ATTR amyloidosis. I'll talk a bit about the diagnosis and staging of cardiac transthyritin 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 can form amyloid fibrils in humans and they form the basis for the classification of the different types of amyloid. 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 non mutated transpiritin or alternatively mutated transpiritin. It is important to determine what amyloid type 1 is dealing with in clinical practice because the different types of amyloidosis behave very differently and they're treated in a completely different manner.
Fibrillation ATTR amyloidosis, as I mentioned, the amyloid fibril protein is unmutated transpiriting. 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.
Now the 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 UK from our national center, and this is true all over the world, particularly in wild type ATTR amyloidosis, the line shown in red there.
Hereditary ATTR amyloidosis, the amyloid fibril protein is mutated trans thyroidine, is dominantly inherited, and there are in fact more than 130 amyloidogenic mutations that are known about of the TTR gene that caused 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 variants 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 UK 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 heart biopsies for patients with cardiomyopathy. And similarly, neurologists 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 at 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 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. 1 is cardiac magnetic resonance imaging or MRI. We first reported a series of 29 patients in 2,005 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 UK, we use DPD, in the US, PYP. And there have been reports in the literature for many years, in fact, several decades of a patient has a bone scan, has cardiac uptake on their bone scan and turns out to have amyloid. And about a decade ago, Claudio Ropetsi, 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 two tests, in particular the DPD or bone scintigraphy, that we came up in a collaborative study with a non invasive diagnostic algorithm for ATTR cardiomyopathy, and I'll take you through it. Essentially, if a patient 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 three 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 gammopathy using those three 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 thromopathy. 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 him 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 LAMDA 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 chart 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 transthyreting or TTR. So this patient had wild type ATTR amyloidosis in the context of an incidental monoclonal gammopathy 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 burn 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 transthyroid in 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 trans thyroid and 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-twenty 12, the line the black line shows improving survival from diagnosis. And in fact, these are patients who do not receive any disease modifying treatment and the symptomatic management of these patients has not really changed. So what that suggests is that patients post-twenty 12 are being diagnosed earlier.
And in fact, post-twenty 12, 70% of patients in our series are diagnosed by non invasive methods and whereas pre-twenty 12, 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 misdiagnosis when patients present with hereditary ATTR amyloidosis and neuropathy, And the average delay in 1 series was somewhere between 2 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 neuropathy 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 UK, is the patient of Irish origin referring to the T68 variant that I 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 an 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 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 trans thyroid and 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 eGFI 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 1 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 NIST, the NIST lower limb score, the NIST plus 7 or the MNIST plus 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 BRAKE 2 or 3 DPD scans in the Spanish study with increasing age. You can also see that among heart patients over the age of 60 who present with heart failure to hospital, 4% turn out to have ATTR cardiomyopathy. And in an American study, 16% of patients undergoing trans aortic valve replacement were found to have cardiac ATTR amyloidosis. So that's the emerging data on 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 in person 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, akaramidis, as you've heard about from Jonathan, or possibly diflunizan. So to summarize, cardiac, trans thyroid and amyloidosis 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 to increase 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 emerging. So I'd like to thank you very much for your attention and acknowledge my team at the National Hemolyodosis Center who are responsible for generating much of the data that I've presented today.
You. Thank
you, Julian, for that overview on ATTR. We're now going to transition to discussing our gene therapy 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 Orenovo and the company's Chief Strategy Officer and Executive Vice President of Preclinical Development. Eric has over 15 years of experience in cell and gene therapy.
Thanks, Christine. I'm Eric David, the CEO of Bridge Biogen 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-six thirty one, our AAV5 program for CAH, which is our focus today and BBP-eight twelve, our AAV9 program for We also have a robust pipeline of earlier stage programs, including one we've announced publicly, BVP-eight fifteen, our AAV program for TMC1 hearing loss. Now we're basically a standalone 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 labs 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. They 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 us 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 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 Wang Ping Gao at UMass, Jeff Holt at Boston Children's and Sandra Breakfield and Casey McGuire at Mass General.
Now when Neil asked me to lead BridgeBio Gene Therapy, the only program was the CH 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 1950s. Yes, we've seen longer acting steroids, but little else. There's some innovation now with the development of CRF antagonists, 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. 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 17 OHP and androgens. Even with corticosteroids, patients can still die of adrenal 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 CEH patients have a 3 to 4 fold higher mortality than the general public. There are full standard deviations shorter than the general public. They suffer from a host of cardiovascular, 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 you know that I'm really old for a CAH patient, that I live 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 non classic that's largely asymptomatic and most of the non classic 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 of mice. Now focusing on that protein expression, we were able to develop a mass spec assay to distinguish the human 21 hydroxylized protein that we were inducing via the gene therapy from the endogenous Sinoprotein. 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 CYNO21 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 Sarafoglu. 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 hyperparecea. Congenital adrenal hyperplasia due to 21 hydroxylase deficiency is a part of 6 autosomal recessive disorders and its leading cause of CA8. In this form of CA8, enzyme deficiency, Rital, in impaired cortisol synthesis, excess anaerobic production and cell wasting in 75% of the cases due to aldosterone deficiency. Because of the importance of cortisol, adrenocortisol production is regulated by the hypothalamic pituitary axis.
Normally, when cortisol levels are decreased, this signals the hypothalamus and pituitary to increase the CTH secretion in order to stimulate the adrenal gland to make more cortisol. However, in CAH, the adrenals are perpetually stimulated by CTH to produce cortisol, which they cannot, so that leads to hyperplastic adrenals and excess production of androgens starting in utero. CAH requires lifelong glucocorticoid treatment. Untreated or undiagnosed CAH can lead to cell wasting and or adrenal crisis, the causes of puberty and sore stature. Untreated CAAs 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 their 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, measurement of 17 ospine and androgens confirm the diagnosis. Molecular testing can also be used to aid in in distinguishing between cell wasting and seaborne license forms.
In childhood, hydrocortisone in 3 dividing doses is the gold standard 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 active steroids such as dexamethasone or prednisone because they require only 1,000 to 2,000 per day. Monitor of the disease control includes measurement of adrenal steroids, electrolytes and REMS to be checked in patients with cell wasting CAH. Monitor of disease control consists of 3 to 4 times a year in children and provides limited information, but that's a discussion for another time. Clinical signs and symptoms to monitor CAH in childhood include weight gain, growth acceleration, bone a rapid bone age maturation, to name a few.
And in adulthood, again, increased weight gain, blood pressure, osteoporosis and signs of insulin resistance should be monitored. Except for some incremental adjustments, 3 44CAH has not had any significant advancements in 60 years. Physicians still struggle to find the right treatment balance to avoid anti treatment, which leads to excess androgen production and overtreatment, which leads to glucocorticoid excess and oversuppression of the SPA axis. Because of the limitations of current therapy, patients have alternating periods of hypocortisoremia and hypercortisolemia every day. Chronic hypocortisolemia triggers increased adrenal undersea production, which can then lead to premature fusion of the growth rate, continuous genital virilization, precocious puberty, adrenal rest, polycystic ovarian syndrome, infertility, to name a few.
Chronic hypercortisolemia because of glucocorticoid excess can lead to osteoporosis, sore stature, weight gain, iatrogenicoustic syndrome and increased risk for cardiovascular disease in other foods. Here is an example of what happens in overtreatment and why finding the right balance is critical. In this clinical case, previous providers focused only on normalized and androgen throughout the day, which meant they gave her higher doses of hydrocortisone that her body needed. So and you can see that she developed cusinoid 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 dosage, it still caused glucocorticoid excess and carcinoid features. Why optimal treatments of Cardioxy? TURO medications do not replicate physiological endogenous cortisol or post type secretion pattern of circadian and neutranial rhythm. Hydrocortisone has the short half life. Low captive glucocorticoids lack positivity and can oversuppress 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, it's even shorter in children with CAH. In this figure, you can see that the normal rates in sated in grape. You can see that the treatment with 3 doses of hydrocortisone caused superficial spikes in cortisol concentrations, quickly followed by rapid elimination with hypercortisolmia between the doses.
Most importantly, the evening dose in children washes out in dairyman monocars, resulting in Nanopost SCTA stimulated adrenalandrogen production. Now the rapid elimination of cortisol within 6 hours after dosing, as you can see here, causing rapid rebound of the adrenal-seventeen Osp and delta-four A concentration levels around the same time. And that's what we saw in our study of 35 patients with CAH. And as you can as our 24 hour simulation model based on PKPD parameters of 67 patients with CAAs shows that even increasing the number of times that you give hydrocortisone, you can see here, 4 times. You can still have periods of hypocortisolmia, and you can see that the adrenal androgens can remain elevated throughout the day.
Now another challenge of treatment that is often overlooked is that normal cortisol metabolism follows both circadian and neutraderythms. In a classic circadian pattern, cortisol concentrations peak early in the morning and decreased throughout the day, reaching its lowest concentration around 11 p. M. In children and midnight in adult. At 2 a.
M, around here, cortisol concentrations 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 autoregressive of discrete cortisol pulses, as you can see here, every 90 to 110 minutes that follow a CTH pulses. The upper panel 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 with tradiarism over 24 hours. Now pulsatile access of glucocorticoids to the settlers has been shown in vitro and in vivo in animal models to be of critical importance for gene regulation, non genomic glucocorticoid signaling, HPA axis regulation and endophenet behavior responses.
The different and often completely opposite effects of falsetal versus continuous form of presentation is well described in other hormone systems. For example, in females, pulsatile delivery of gonadotropin releasing hormone induces ovulation, where continuous delivery results in an ovulation and suppression of the hypothalamic pituitary conadal 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 1st study to quantify the effect of hydropotulin dosing on final adult height. Now this figure illustrates that even hydrocortisol doses in the recommended rates between 10 to 15 milligrams per meter square per day, a negative effect of hydrocodone or height, it can still be seen, suggesting that other factors such as positivity, utradian and cicada rhythm, timing and frequency of hydrocortisone dose, sensitivity to glucocorticoids and individual Cortisol Pharmacokinetics and Pharmacodynamics play a role in optimal adrenosteroid control and attainment of final adult high.
The take home message is that current therapy does not reproduce endogenous cortisol production rates nor replicate circadian and atradia cortisol secretion. However, what current therapy does do is expose patients to alternate periods of hypo and hypoportisolemia, all of which result in some optimal short and long term outcomes. What is needed to improve outcomes in CIH? You need a therapy that is based on a 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 cikardian and tradia secretion of endogenous cortisol.
Thank you, Kiki. We'd now like to transition to our next program talking about in Kelseyret 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 Ncalerate for disorders of calcium homeostasis, including the autosomal dominant hypocalcemia type 1 or ADH1. Encalerate 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 Doctor. 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 CALORET.
It's been well tolerated in over 1200 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 Phase 2 study in ADH1 is planned to initiate in 2020 with proof of concept data anticipated in 2021. Encalorant has potential to be 1st 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 is 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. Encalerit 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 sensitive 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, initiates signals that act to reduce calcium. And if the calcium is too low, it does the opposite. So these mutations make for an hyperactive sensing mechanism that basically tells the target organs of the calcium sensing receptor that low calcium is sensed as normal or normal calcium is sensed as 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 Ncalerate for ADH1 is by reducing the sensitivity of those mutant receptors and that is designed to stimulate PTH secretion, allowing it to act to 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 PTH 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 by.
And CALORET is designed to target ADH1 at its source by normalizing the hyperactive calcium sensing receptor. So the rationale for studying the calcylitic NADH1 is because, as I said, it's a perfect fit between the molecular pathophysiology of activating mutations causing the disease and the primer the 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 in CALURET normalized serum and urine 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 INCalURET also increased 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 2 open label dose ranging study in patients with ADH1 to evaluate the safety, tolerability and efficacy of INcalARET in normalizing serum calcium and urinary calcium.
We're planning to study up to 16 ADH1 patients at the NIH clinical center with 3 periods of inpatient treatment and one period of outpatient treatment with respect to dose escalation and evaluation of the ability of encalarad to achieve its therapeutic goals. So the primary endpoints, again, this is a Phase 2 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-twenty 21. I'd now like to introduce Doctor.
Michael Collins, who is 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 is the corresponding author on the publications of calcium sensing receptor antagonists in the context of ADH1 and is both our clinical advisor 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 Inoccalarette 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 in the diseases and the patients, a bit about the calcium sensing receptor antagonist and specifically how we'll use them to treat ADH1. But first, why is calcium so important?
Probably needless to say, it's important in cell signaling and neurotransmission as a cofactor for enzymatic reactions and 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 for 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 calciostep. 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, monized 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 calcium sensor 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 kidney as
we'll see.
It's this property of the calcium sensor 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.
And it's expressed in sometimes in the apical or urine side of the tube and sometimes in the vasolateral or blood side of the tube. And this allows the calcium sensory receptor to have exquisite control over the reabsorption of calcium in the urine. Calcium is all filtered at the glomerulus, 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 calcium mimetics and calcilytics.
So what are the diseases of the calcium sensing receptor? 1 is familial hypocalciuric hypercalcemia. This is caused by loss of function mutations in the calcium sensor receptor variant. In this mutation, the calcium sensor receptor thinks that blood calcium is low and the dose response curve is shifted to the right, as you can see here. In this condition, you have increased parathyroid hormone, increased blood calcium and relatively lower urine calcium.
I 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 due to gain of function mutations in the calcium sensing receptor variant. And in this case, the calcium sensing receptor thinks that blood calcium is high, dose response curve is shifted to the left, we have low PTH, low blood calcium and relatively high urine calcium. This is one of the biggest problems with 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 and 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 calcitriol, which is a form of 125b. Throughout his life, he's had frequent pamping, peristiges and occasionally this fogginess.
Shown here are some of the complications that he's 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.
It's not completely clear if this has really any clinical sequelae. 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 of ADH1 is good.
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 gets along pretty well and 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 one of the big problems with hypoparathyroidism, 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 effect of
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 these patients. So this really very much is a disease where you're walking a tightrope 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 the better treatment?
The better treatment we think is calciolytics. What are calciolytics? So calciolytics and calcimimetics are agonists and antagonists to the calcium sense receptor. As I said, this calcium sense receptor was discovered in 1993 by Ed Nemeth and Brown. By 1996, Ed Nemeth and other scientists at NPS Pharmaceuticals had discovered the first calcimimetic, an agonist in the calcium sensitive receptor.
They then described a few years later, antagonists of the calcium sensitive 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 hyperparathyroidism 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 when I was a trainee.
I was an endocrine fellow here. We admitted a patient in 1996, a 78 year old man with widely metastatic parathyroid cancer. He was abundant, unresponsive to conventional therapy. There was really nothing for this man to do. So I had heard about NPSR568 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 Neiman, 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 MPSR-five sixty eight.
And the response is shown here. It was really dramatic. He had an immediate response to the drug. We increased the dose of it 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 agonists of the calcium receptor could work. So what was next?
NPS licensed calcimimetics to Angen. They went on to develop Senecalcit, Sensipar, and it's become approved for secondary hyperparathyroidism in 2,004 and parathyroid cancer in 2,001. What about calcilytics for ADH1? Here's a brief history and a bright future. So calcilytics really do represent precision medicine for ADH1.
Calcilytics increased PTH, which was thought initially that it might be a good treatment for osteoporosis, like the drug teriparatide. 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, ronocalaret, 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 rona calorit in ADH1.
As I
said, the drug failed in 2,008. 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. We started a study for ADH1 approved 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 of 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 calcimab. This will help restore blood calcium. So with that, we were eager to continue. 2015, however, Shire Pharmaceutical acquires MPS. Everybody that was on the Castlelytics teams leave Shire and interest is lost.
2019 Shire is acquired by Takeda, even less interest. So it looks like Castlelytics were dead for a while. That brought us to 2018 and BridgeBio came and visit us here at the NIH in regard to a study with infragratinib 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 Calcelytics might be something that RidgeBio 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 and 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 post surgical 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 xenotype. 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 Gaffett. 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 Neiman. 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 Poza, who's the research nurse
on this 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. 2 other physicians on the study, Iris Hartley and Kelly Roscoe. Of course, the Calcelytics team, Michael Henderson, Eric Gomez, who was the one who did the due diligence on Calcelytics, Jonathan Fox, the medical lead on this Rami Sanegrosso, who it's been a pleasure to work with Anant, 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 NPSR568 study going, which was the basis of why I'm here today. And with that, I'll close and take questions.
Great. Thank you, Doctor. 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 residence 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 1st in class HIF2 alpha inhibitors, which were previously believed to be an undruggable target. Those have shown excellent activity in both 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 benumitinib for melanoma, selumitinib for NF1 and tucatinib for breast cancer. Joining me on our senior oncology research teams are Doctor.
Pedro Beltran, who has over 20 years experience in cancer research, drug discovery and development obviously, Professor Frank McCormack and Doctor. Richard Scheller, who is our Chairman of R and D. Now I'd like to spend just a minute telling 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 programs forward in a model that has proven very successful in my career. And BridgeBio allows me to do that in an environment in which is part of a larger organization. So I get both the advantages of a small biotech, but with the important backing and resources of BridgeBio more broadly, which includes obviously scientific expertise, but also with the resources need 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 SHIP2. SHIP2 is an optogenic phosphatase that drives cell growth and 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 BPP398, a novel SHP-two inhibitor that we have optimized for both safety pharmacokinetic and pharmacokinetic 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 3rd 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 or GPX4. GPX4 acts to detoxify these peroxide lipid 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 our 1st in class oral inhibitor of GPX4. As I think is well known by this audience, our RASP 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 NCI 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 3rd 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 KRAS 4b. 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 to 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 programs 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 targets H95, a novel residue 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 present 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 3rd, 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 and 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 pobaciclib. 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 finish up 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 are 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 really need 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 to redundancy of the RAS proteins themselves.
The left wiring diagram, which you won't be able to see in detail, just makes a point that RAS proteins in the circle there are part of a very complicated signaling network, which sends signals from all growth factor receptors into the cell to tell them to divide. So all cells depend on RAS proteins for their proliferation and their survival. At 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 MEK and ERK. These are druggable targets and there are great drugs that have been developed, including by Eli. But when these drugs are applied to RAS cancers, have not been effective because of the complexity of the signaling network.
And on the right hand side, just to make the point that RAS proteins are part of a 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. From the 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 inactive state.
Let's run this animation again. You can see protein switching back and forth from the 2 states. But the surface of the protein does not have any deep pockets which a small molecule can easily bind. So it's been actually 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 in just a moment. Our RAS proteins function in the 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 the membrane prevents it engaging with other proteins and then turns off the protein's biological activity. And that's the basis of our first approach to targeting 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 a Farnosol group or a Geronorgenol 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 C there is a cystine to which farnesyl or germinogenermal groups are modified to localize the protein in the plasma membrane.
So our first approach is to find compounds, which covalently attack that cystine and therefore prevents modification of KRAS by other pharmaceutical transferase or general general transferase. And the compound is expected to bind somewhere on the surface of the squishy tennis ball and then covalently hit the cystane as the floppy tail flops around. This simulation shows that 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 on the right panel here, bind into a little groove in the KRAS protein. And then the yellow blob on the top left is the cystane from the end of the C terminal tail.
When this flops over into the G domain, the tennis ball path of protein, we see covenons attack on the cystane, which irreversibly blocks the C terminus of the KRAS protein and prevents thionylation or general generation and therefore prevents the RAS protein accumulating in the plasma membrane and kills 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 the plasma membrane, as shown in the left hand panel by Western Bluff 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 cells to prevent KRAS processing and shutdown KRAS processing as a result of failure to localize in the plasma membrane. So that's the basis of our first approach, preventing newly synthesized KRAS from getting thonisylated and processed and therefore keeping it in the inactive state.
Now as we were looking for 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 2nd major projects in this area. 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 that exposure to this compound in a pancreatic cancer cell line destroys KRAS protein. This drug is not working by preventing newly synthesized KRAS coming to the membrane, instead it hits the fully processed mature protein. And first, we could not understand how this was working, but through our collaboration with our colleagues at the Frederick National Lab, we were able to figure out that this compound actually reacts with a histidine in the RAS protein, not the cystine as we'd originally anticipated.
Now this we found extremely interesting because the histidine residue, which this compound targets is actually unique to KRAS. From the bottom of this slide, you will see a series of amino acid sequences of the HN and KRAS proteins. And you can see in red highlighted the histidine, which is unique to KRAS amongst all the superfamily of RAS proteins. So this histidine is actually amenable to attack by a covalent 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 in the middle of the protein there sticking up on the edge of that helix. It's right by the switch to pocket where the G12C compounds that have been developed by Amgen and Marathi and Janssen and Genentech. Their compounds bind in that pocket, but their compounds only bind to the inactive form of the RAS protein. This is a gene 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, 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 Frederick 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 and 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 time zone issues, but we have all of our other speakers here today.
And just as a reminder, in order to submit questions, you do need to be logged into the webcast. So we're going to get started with 1 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 the 20 programs under development, how do you prioritize them and what has been the attrition rate from preclinical to clinic?
Yes, Dave. Well, let me again thank all of our
speakers, learning a big deal and everyone who's taking the time to dial in this morning. I'll be brief because I'm keen to learn from our terrific team and our talented collaborators. It's a great question. Actually, we don't think about prioritization from a a portfolio standpoint. There's 2 different ways one can view a collection of projects.
1 is from the portfolio view where you set some sort of 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 and continues to be valid in terms of the therapeutic hypothesis and the science being strong, lung 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 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.
Pre clinically, our historical POTS has been around 83%. It's something we measure quite closely, although I will say that 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 one of 3 parameters we look at globally to judge our performance. We look at POTS, we look at dollars to IND, which obviously is a reasonable marker of our efficiency.
And we look at number of new programs, we did 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 POTS being 1Q1 there.
The next question comes from Tyler Van Buren, Piper Sandler. His question is for William Gilmore. How has the diagnosis rates and technetium scanning increased with the tafamidis launch so far? What fraction 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 UK, 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 UK and then subsequently down to increasing use of bone scans. Since Tafamidis and since the results of the ATTRACT 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 number that's resulted in an ongoing increase in terms of number of diagnoses.
But I think the awareness had actually started beforehand. Having said that in answer to your 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 is quite 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, the 4% of patients with over the age of 75 with HFF 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. Okay. 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?
Yes. Hi, 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 dot 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 enrollments 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 and Mizuho. Everything we have seen has shown apiramidis 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 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 match controls. What we've seen in the ATRAC data is a very encouraging signal of slowing of that decline that was apparent even by the 12 month time point in that study according to the publication in New England Journal back in 2018. And that was what inspired us to create this embedded design of the Tribute 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 market 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 AKERAMATIS, we think is going to be better than the result that you saw with TEGARAMATIS.
Yes. Just to put a
I think that's very well said, Jonathan. We consider the ATTRAC 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 and progression.
Great. I think the next question again is from Celine for you, Jonathan. If you have near full TTR stabilization, mechanistically, is there a place in the market for TTR knockdown therapeutics?
Yes. 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. 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, 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 Manny at Leerink. This is for Susan. Could you please comment on the enrollment of the PROPEL-two study?
And are there any restrictions or stratification by ex GFR3 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-two study. The delays were mainly in the March, April timeframe, but recently the impact has been much less and enrollment has pent up and we are really encouraged by the enrollment rates that we're seeing. And as we mentioned, we've dosed the 1st patient in PROPEL-two.
95% of these patients will have the same point mutation and the children need to have documented FGFR3 mutation. So we don't expect there to be a variety in the genetics of these children.
Great. Thank you. So 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, infaratinib 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 path pathways instead of only 1, we believe emfogratinib 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. We think that this could be a meaningful advantage for parents and for children.
Great. 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 published the results of their Phase 3 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.
Okay. Thank you. The next question actually brings us to the CAH program. So this question comes from Paul Choi at Goldman Sachs. Eric, David, perhaps you could start us out with this question.
What levels of endogenous cortisol production would constitute success for the gene therapy
program? Hey, this is Eric. Thanks so much. And this is a great question. Classic CAH patients make very little cortisol at baseline, so usually in the 0 to 3 microgram per deciliter range.
And we'll be measuring pretreatment baselines on all the patients. So any statistically significant increase in cortisol levels above that pretreatment baseline would represent a really promising early sign of functionality. And then the dose expansion will let us see how that level increases with dose. So the beauty of the study design, it allows us to look at these endogenous cortisol levels and the production in patients and then taper steroids in a safe controlled setting and assess exactly how much. But really once it's above baseline, we'll go with the dose escalation and see where we go from there.
We'll be able to see exactly how the patients are doing off of their steroids on it.
Great. And then the next question again on Kiki, you could also answer this question. What do you view as the main differentiator with the CRF1 antagonist?
Sure. I'll kick it off and then turn it over to Kiki. But I'll simply point out that most of Kiki's talk focused on why restoring the body's own ability to make cortisol really matters. Only a gene therapy will allow patients to produce their own cortisol and mineralocorticoids on demand, again, in the right amount and at the right times. So and look at this, the wonderful review article on CAH in the New England Journal in the current edition by Debbie Merck and Richard Aukas, who we're also working with, you can see all the clinical manifestations of the disease and laid out and there's a figure in there, figure 3 that shows which are attributable to steroids, which are attributable to the disease itself and which combination of the 2.
Only a therapy that can restore the body's own ability to make cortisol and mineralocorticoids can have a chance of resolving all of these issues. So it's really a game changer. Look, we are thrilled for any innovation for CAH patients because there has been so little of it to date. So CRF antagonist can play a role. They've been shown to reduce 17 OHP and androgens.
We'll see if that translates into any reduction in steroids. But CRF antagonists cannot get patients off of steroids or mineralocorticoids and can never enable their bodies to make these. So, Piki, I turn it over to you.
Yes. Eric, I couldn't say better than you did.
And so what I have
to add is that, yes, the CRF agonists are important right now because we it's an adjunct therapy to what we have right now, which is not optimal. So it has the place when someone is on oral hydrocortisone dosing because we know that there are periods in daily morning hours where the androgens are high and that's what the CRF agonist try to address. But having endogenous cortisol is a game changer because then your body is going to make its own cortisol and your body is going to respond to a CTH to make more cortisol when your body needs it, for example, in the early morning hours or during stress or during physical activity, something that right now we can because we give 3 doses or 4 doses, but still as my slide show, we still have the issues. And unless we have a way that we can we have a therapy that follows circadian and neutrinoism, we are going to continue to have the adverse side effects, long term side effects that we see. But of course, we welcome anything right now that can help the therapy, what we have.
But gene therapy, if it works, that would be a game changer.
Great. Thank you. So our next question takes us to our ADH-one program and this is a question from Tom Schroeder. This is for you, Doctor. Collins.
Could you discuss the similarities and differences between ADH1 and postsurgical hypoparathyroidism? Is there a reason to believe in agonizing the calcium sensing receptor would be useful in this broader population?
Hi, thanks for that It's a critical question, I think. The main difference is physiologically between the two is that of course with postsurgical hypoparathyroidism, there is no parathyroid gland and there is no effect of the calcium syncytic receptor there. The only effect will far and away the most important effect will be at the kidney. The effect of the kidney will be to retain calcium in the blood and decrease calcium in urine, which is the main problem in the treatment of hypothyroidism. If you recall from the slide that I showed that walking the tight growth and the importance of raising calcium and lowering urinary cancer.
In fact, raising blood calcium is in some ways relatively easy and any and all of the drugs including conventional therapies that we have do that quite readily. The big problem and what causes long term morbidity and even mortality in these patients is renal damage and renal failure and hypercalciuria. So parathyroid hormone replacement can address that, but we don't think adequately to the degree that a calcium a receptor in secondary. So the big difference will be in this drug, we're in conventional therapy, I think this will also apply for surgical hypoparathyroidism is you'll be able to raise the blood calcium more comfortably into a normal range. Part of that would be calcium sensitivity receptor itself.
And in so doing, you'll minimize or eliminate hypercalcicure thinking this is the goal and this is what I think we'll do in the future.
Thank you. The next question again is for you, Mike, and it comes from Tyler Van Buren. Can you please talk about the prior development of eCounterSorAbs and why was it only modestly effective previously? And what do you why do you expect it to be different this time?
So just can I have the question clarified again, please?
Sure. So why was an earlier talcolytic only modestly
previous therapy fell short was simply a measure of exposure. This was the first time it was a proof of concept study and the goal was simply see if we could affect the parameters that we were hoping to see. The dose of the drug was far and away inadequate to bring about the results that we are looking for. Part of that was intentional. Again, this is first disease with the students who are being very cautious, but the thing we thought was effective.
So the main reason why this drug will be different is that we will have much of our exposure to the drug. We know we can safely escalate the dose to higher doses to see the effect and get the effect we hope to get. And the other thing that makes this more likely is I really think that the guys at
that
that were around. So this particular drug, this calcilytic probably had one of the worst profiles for the treatment of osteoporosis, which makes it the best profile pharmacists in terms of its efficacy for
Okay. Thank you. Next question is for Jonathan about ADH1 program. What top line results are expected in 2021?
Well, I think as we outlined in the slide presentations and Mike elaborated on in his talk, the main endpoints really are all about blood calcium and urine calcium. So there will be a bunch of secondary endpoints and other biomarkers, but those are the 2 main readouts of that are not only the most clinically important ones, but the ones most likely to establish proof of concept and ultimate therapeutic success for the program.
Thanks. The next question takes us to the target oncology program, and this comes from Tyler Van Buren. And this could be for both Frank and Eli, what gives you confidence that you'll be able to achieve similar or better potency with a pan KRAS approach relative to the KRAS mutant specific approaches?
Okay. I can take that. Yes, I think the benefit of our approach will be we can apply this approach to knocking down all mutants of KRAS, not just the D12C. We agree that our surveillance approach is ideal for the reasons I discussed in my talk. But in this case, the covalent attack is not on the residue that actually causes the mutation that activates the protein, but actually is in a unique residue in the KRAS protein.
So we get the benefit of having a covalent attack without the restriction of having to target very specific amino acids, which caused the mutation, but are not considered to be likely to be attackable by covalent inhibitors.
Eli, did you want to comment too?
No, I think Frank hit it. I mean that's one of them. The other approach that we touched on briefly, it's hitting the effector interaction, which will also be mutant agnostic and I think really be differentiating versus the other approaches that are out there today.
Okay. Great. That's kind of an interesting question for you, Eli. What about your efforts at BridgeBio's heart and oncology are similar to your efforts at Peloton and Array that could lead to similar success?
Yes, I think there's a few parallels. I mean, I think I touched on it a little bit in my remarks. We BridgeBio is a large organization, but as I think Eric David put it well when he talked about the gene therapy approach, we're kind of an independent standalone entity within the larger environment of Bridge. And that allows us to really have the focus and drive an autonomy that is successful in discovery efforts within biotech and has been the case both at my career at Array and at Peloton. And I think another important parallel and one that Neil talked about and described very well is Bridge's model to collaborate with these centers of disease excellence or academic centers and the RAS initiative and our work with them at Frederick National Lab and our collaboration with Lawrence Livermore National Labs are a great example of that and something that we did at Peloton as well where we collaborated with UT Southwestern Medical Center to push FIFTA forward, that was thought to be undruggable.
And I think it's a very similar strategy in parallel with the RAS initiative and our approaches to RASH where the structural biology and expertise from Frederick, couples with the Lawrence Livermore National Lab Computing Power and Molecular Dynamics. And then the last piece of that stool is, of course, our drug discovery expertise that we bring from years of experience at Array and Peloton and others.
Great. Thank you. We have another question on KRAS from Dane Leone at Raymond James. Can you provide more insight into the therapeutic index of a pan KRAS inhibitor? Seems like the field has been skeptical of the tax penalty for KRAS wild type inhibition.
Yes, that's a great question, Yale. Well, this approach has been validated by Mariano Barbases in Spain, who has made knockout mice in which you can ablate KRAS in an adult animal and shows that ablation of KRAS has no serious side effects in an adult in normal tissue. And that's because in adult tissue, HRAS and NRAS in normal tissue can actually act as a kind of backup for KRAS because they're redundant. So it looks like ablating KRAS is safe as long as you have HRAS and NRAS as backup.
Great. Thank you. So now we have a couple of interesting questions kind of more broadly. So another question actually from Dane Leone, which is some of the programs that we've got today are focused that we focused on today are advancing the later stage clinical testing and this question is for Neil. How do you think about retaining in house ownership versus partner?
Yes, great question. So I think broadly, we're interested in the global distribution of the medicines that we create. Obviously, not all of them will be at scale such that it's ROI positive for us to distribute them in all geographies and we pay attention to that on a medicine by medicine basis. There are also certain geographies where we don't feel we could be the best owner of an asset. For instance, we recently struck a deal in a broad deal in the context of the China market with a team that we think is best in class and could get our drugs out against a wide variety of indications there.
So but by and large, we'd like to retain ownership. We think you hold on to more of the NPV if you can commercialize, self commercialize certainly in the EU and other large markets across the world. And I think it's been proven by many of the orphan drug distributors and developers that a large part majority of the sales actually comes ex U. S.
So. The next question is from Adam Hartman with JPMorgan. As we're all looking into the 2021 readouts for many of these programs we discussed,
Very, analyst, question. Yes, I think it's I mean, first of all, obviously, the win scenario is a safe and effective agent for patients that can add to the armament that physicians have within each of these diseases. So let's just walk through the four value drivers, Nup, as you'd want to. On ATTR, I think as we spoke about earlier, we'd be looking for a less than 50% slowing effectively of against 6 minute walk. I talked a little bit earlier about the decline that was shown from tafamidis.
I think I misstated it and said at 30 months, but at 12 months, it's about a 26 meter decline. So we'll be looking for a significantly less decline on folks or at the baseline of 3 50 years or so, which has been fairly consistent across a variety of different natural histories and the ATTRACT trial. In the context of achondroplasia, I think Susan said it exactly right. We'd be looking for a demonstrated effect well above the 1.6 centimeters per year that vosoritide demonstrated. And yes, that I think is both demeritabole and we'd be looking for something that's statistically significant there.
In the context of CAH, we'd be looking for endogenous cortisol production. We'll have to see what the baseline looks like and others can comment on the phone in greater detail. But I think typically these patients have between 0 and 3 microgram per deciliters in terms of a baseline. And so we would be looking for a statistically significant increase against that certainly above 5, I think would be the starting point where we start to get excited and hopefully up into the 10 plus range. And against ADH1, we'll be looking for those dose dependent increases in serum calcium in PTH and a decrease in urine calcium levels.
So fairly straightforward, I think, and Yifan, we'd be happy to connect as well just a little bit more on kind of the statistics that we can and can't see and what the power looks like based on each one of these trial designs. But good question.
We have a couple more questions on the ATTR program. So this one comes from Greg Harrison at Bank of America. This one's for you, Jonathan. What factors caused the change in the APHEREITYCN trials and the recent update where we projected enrollment completion in the first half of twenty twenty?
I'm sorry, Christine, could you repeat the second half there? My connection is not great.
Yes, sure. So the question is basically asking what factors caused the change in the enrollment completion for TributeCM where we now have the potential to have data earlier than we were initially guiding towards.
Okay. Yes. Now I think I understand the question now. Well, I think the big uncertainty that we faced in recruiting to the trial was COVID-nineteen. Some of our best enrolling centers like Julian Center in the UK, the centers in Italy and in Spain were all hit pretty early by the pandemic and were hit quite hard.
We still have concerns about the ability of those centers to continue to follow-up given the uncertainties that remain with the pandemic. But I have to give a lot of credit to number 1, the participating patients, their families who support them and the investigators and their staffs who have devised a number of workarounds and have remained very flexible in being committed and dedicated to the completion of the trial. So to the extent that we rely on that source of energy and enthusiasm that has really propelled the enrollment once the some of the restrictions that were early on in some of those countries regarding COVID-nineteen were lifted and allowed people to come into the trial.
Great. Thanks, Jonathan. Next question comes from Paul Choi, Goldman Sachs, and this is for Julian Gilmore. Just about the 6 minute walk test. Many of the new trials in HTRCM are using the 6 minute walk test as a functional outcome for their pivotal studies.
Do you measure 6 minute walk test in your routine practice? And is it an endpoint that will be useful for patients and physicians?
Yes. So, thank you for the question. I think it is well, so first of all, we do routinely measure it every time a patient attends our center. And what we do see is a fairly consistent decline
in patients
with ATTR cardiomyopathy, as endpoint. I mean it would be nice to know if we have a better endpoint at a shorter time point, if you like. But at the moment, I think it's the best thing we have. And we have the ATCK trial data, which you all are aware of, which looks encouraging. So I think it's a very reasonable endpoint to use, particularly for cardiomyopathy studies.
I think one thing that's just worth mentioning is using it for a patient with a mixed phenotype hereditary ATTR amyloidosis who has both cardiomyopathy and neuropathy may be slightly more complicated. If they have very significant neuropathy, obviously, that could contribute to the decline or otherwise of the 6 minute walk test. So I think that becomes a bit more complicated. But in patients who have dominant cardiomyopathy, I think it's a good endpoint, yes.
Great. Thanks, Julien. Okay, great. Well, that concludes our question and answer session today. Again, I'd like to thank all participants today.
And I'm going to turn it back over to Neil for concluding remarks.
Yes. I'll be brief. I just, first of all, I wanted to thank everyone, the speakers, both external and internal for their time this morning and everyone who's been on the line listening. These comments will obviously be up on our website well, so people can review them. But our hope is that together with your support in this upcoming year 2021, we'll be able to demonstrate the productivity of our drug discovery and development engine and hopefully deliver some really promising clinical data that really matters for patients.
So thanks again for your time and we look forward to following up with all of you in the weeks months to come. Stay safe and happy.