Good morning, and welcome to BridgeBio's 2nd Annual Virtual R and D Day. My name is Grace Rao. I'm the vice president of communications at BridgeBio, and I want to thank all of you for joining us for this event. We have an incredible agenda ahead of us today. We're going to be hearing from Richard Scheller, our chairman of R and D, who will provide some opening remarks about human genetics and the important role that it plays in drug discovery.
Next up, our founder and CEO, Neel Kumar, who is going to be talking about what he calls BridgeBio's endless summer. You'll also hear from Cameron Turtle, our chief strategy officer, who is going to be sharing an overview of our cardiorenal work Before we take a deep dive into our cardio renal programs, starting with our progress on transthyretin amyloidosis, known as ATTR, which is an underdiagnosed, rapidly progressive and ultimately fatal disease. In that session, we will be joined by Jonathan Fox, chief medical officer of BridgeBio Cardio Renal, who is going to be setting the stage for our upcoming top line phase 3 data readout for Akaramatus, our TTR stabilizer for ATTR. The next cardio renal session will be presented by Mary Scott Roberts, our senior director of clinical development at BridgeBio Cardio Renal, who will provide an update on ENCALRIT, our calcium sensing receptor inhibitor for autosomal dominant hypocalcemia type 1, also known as ADH 1. We'll be hearing from a number of senior leaders who work across our diverse pipeline, including Eric David, the CEO of BridgeBio Gene therapy who will be sharing an overview of our gene therapy platform.
Uma Sinha, our chief scientific officer, will provide an update on 3 early to mid stage Mendelian programs. And Eli Wallace will be sharing some news, exciting research developments that are underway in our Precision Oncology Pipeline. He's our chief scientific officer of BridgeBio Oncology. And Charles Holmesy, Chairman of Pharmaceuticals at BridgeBio will be introducing BridgeBio X, our new early discovery research program. Finally, to wrap things up, we will hear from our CEO, Neel Kumar, once again for some concluding remarks.
Before I hand it over to Richard Scheller, I just want to remind 3:1 that today's presentation is expected to run until about 10:30 a. M. Eastern, followed by a 30 minute moderated Q and A that will begin right after the presentations. We do ask that you limit your questions to the topics discussed at today's R and D Day. A replay of the event will be Global on our investor website, and the slide deck from today will be posted there as well.
As a reminder, we will be making forward looking statements, which are based on our current expectations and beliefs. As such, these statements are subject to certain risks and uncertainties. I encourage you to consult the section entitled Risk factors in our most recent annual report on Form 10 ks filed with the U. S. Securities and Exchange Commission and in subsequent filings made by us with the SEC, which are available on the SEC's website.
In addition, except as required by law, we disclaim any intention or responsibility for updating or revising any forward looking statements made today in the event of new information, future developments or otherwise. And with that, I would like to turn the session over to Richard Scheller, who will begin with an overview of the human genome and talk about how BridgeBio is uniquely positioned to drive the development of transformative medicines to treat genetic diseases and genetically driven cancers. Richard?
Over 2 decades since the first draft of the human genome was presented, prior to that, we knew the alphabet of DNA, which was quite simple, only contains four letters, a, t, g, and c, called nucleotides. The project determined the order of the nucleotides and revealed the 3,400,000,000 base pairs. We determined from the sequence that there are somewhere between 2,102,000 protein coding genes. The proteins are the major components of our cells. It's interesting that even today, there's still a little debate about exactly how many protein coding genes there are.
The DNA contains not only the information to build the proteins, but the information on how to put those proteins together to make cells A little bit like the blueprint of how to build a house. For instance, some proteins are made only in the liver, Others only in the heart, only in the brain, and so on. And much of the research that goes on today is to understand how these proteins work and how this blueprint puts the proteins together To make our bodies. Some of the other kinds of research that's going on today has been to determine The sequence of many different individuals so that we can understand the differences Between us, and I'll talk a little bit more about that as we go on. Other research that's going on has been to determine The DNA sequence of many different kinds of living things, including plants, mostly food crops, like rice or corn and many, many other animal species as well.
It's interesting That the human genome differs from our closest animal relatives by approximately 50,000,000 changes. Chimpanzee, of course. 50,000,000 may sound like a lot on the one hand. However, Our genomes are 98.5 percent identical to the chimpanzee. These three fellows are very rare individuals.
They are identical triplets. So they are the progeny of a single Sperm and a single egg. So why do they look so similar? Why don't they look like me or you? Well, an easy answer there.
Their DNA is essentially completely identical to each other. About 4 to 5000000 variants with African genomes being interestingly the most diverse. So we're 99.8 percent similar to each other. Why are the African genomes a little more diverse? Because Humans evolved in the continent of Africa.
And as human migration took place, a few people left Africa To migrate up into Eurasia and to populate the rest of the world and left behind within the continent of Africa, Tremendous diversity. So a major reason then that I don't look like you It's because my genome, as I said, is different from you by about 4 to 5000000 variants. We're not here to talk about why we don't look the same. In the same way that the DNA sequence determines a lot about our features, Our DNA sequence is important in determining our disease susceptibility as well. And of course, that's our our major interests at BridgeBio.
So we are investing in computational genetics and academic partnerships to determine 2 types really of disease variation. The first type is a monogenetic target, and that's illustrated below with the circles and squares. So this is, on the left, a family tree and the filled in boxes in circles Illustrate individuals that have a disease. So as a male and female gave rise to progeny, In this case, the female had the disease as you can see by the filled in circle, and then other individuals, other progeny had the disease as well. So it's not so easy to just sequence the DNA and determine what the variant is that causes the disease because remember, as I said, we all differ from each other by 4 or 5000000 positions in the 3,400,000,000 nucleotides of our DNA.
So by sequencing different individuals in a family tree. 1 can look at the sequence and then hopefully determine Which change it is that gives rise to the disease. Sometimes one has to look at multiple families in order to figure this out. But the point here is that those individuals that have this change with almost a 100% certainty have the disease. Another common form of genetic investigation It's called the Genome Wide Association, which is shown on the right.
And what's plotted here Are the millions of variations across the different chromosomes. You can see chromosome 1, 2, 3, 4, 5, etcetera. And in this type of analysis, what we do is to look at people with a certain condition And understand, for example, that perhaps 60% of the people with the disease have a variant, Whereas maybe only 20% of the people without the disease have the variant. We then do various statistical tests to determine whether this is significant. And if so, then this variant Must have something to do with the disease because it's present more often in the folks with the disease types of analysis Over the last couple decades, there are hundreds of monogenetic diseases, that have been understood in terms of the mutations are the variants that cause the disease.
A couple of years ago, I looked and it was a case That there was more than 1 monogenetic disease being understood per day, such that they're now Over 5,000 of these monogenetic diseases where the disease causing variant is understood. And common disease associations, as I described in the GWAS studies, are rapidly increasing now at an prudential rate, such that there are many, many hundreds of thousands of variants involved in various diseases. I think there are probably over 4 or 500 variants that have been associated with diabetes, for example. So we think we're at a very special time In the history of life science and drug development and that there's a convergence of genetic information Which is driving drug development through the many large DNA databases that exist in the world, which we work with. And it's also the case that there are now so many interesting drug modalities that didn't exist years ago.
Years ago, you usually thought of a small molecule pill or perhaps an antibody injectable therapy, But we now have oligonucleotides, gene therapy, and many other ways to potentially correct The mutations that give rise to disease. In addition, there are a huge number of new technologies that are helping with drug development. Many of these are structural biology based and many other technologies that just make it a great time to be doing drug discovery. So we're very excited about the the future of being able to help patients, Particularly with genetic diseases to lead better lives. And our next speaker is our CEO BridgeBio, Neel Kumar.
Thank you, Grace, for the introduction, and thank you to Richard for his welcoming remarks. I'm very privileged to add my welcome to those of you joining us for our 2nd ever R and D Day. Research and innovation is how we serve patients at BridgeBio and and we look forward to this day every year. As Richard alluded to in his welcoming remarks, we are amidst a true revolution in our understanding of genetics, genomic science and molecular disease. As Simon Winchester points out in his terrific book, The Perfectionist, No industry can truly undergo a revolution without the tools and associated processes that allow one to elevate precision.
Today, with our ability to identify novel variants, including structural variants, to connect them to functional consequence, To identify mutations and to predictively model and biochemically assess them, connect them to protein dysfunction, And to put that protein dysfunction in the context of cell type specific biology and ultimately to put all of that biology in concert with symptomatic and disease level information. There can be no question that this industry has reached an inflection point company is putting yourself in and around inflection and innovation such as this. And at BridgeBio, we are extremely lucky to be partnered with the academic institutions and many of the academics that are responsible for innovation of this ilk. The second ingredient toward creating a great company is ensuring that you're taking all of that innovation and pointing it at problems that matter. As Richard alluded to, genetic disease in concert is a problem that matters, affecting some 25,000,000 Americans alone and affecting them with a great degree of disease severity.
There are some 8,000 genetic diseases out there with only about 50 approved therapies. And even those therapies aren't the last word in the game for patients, there's a lot of important work to do in this sector. And the innovation in concert with the unmet need Are 2 of the key ingredients toward creating a great company. They're necessary, but not sufficient. There's a third ingredient that many of our biotech brethren don't speak about and many of our colleagues in big pharma don't talk about either.
But it is the creation of a corporate model, an ecosystem that allows one to work on many of these programs at the same time and over a long period of time. Now you might ask me, doesn't such a corporate structure already exist? Aren't the oil wells of innovation already open with all of the dollars we see flowing in to biotech these days and all of the research dollars that are being appropriated by large pharma. Sadly, The answer is no. If one were to look at my first chart here on the left hand side, you can see that return on invested capital for large pharma Across the aggregate of its R and D activities is unfortunately lower than its cost of capital, further suggesting that every incremental dollar spent by large pharma On research, ultimately destroys value for shareholders.
On the right hand side of this slide, you can see the picture being no rosier in biotech, Where an aggregate market capitalization of almost $1,400,000,000,000 in SMIDCAP suggests that we need almost $40,000,000,000 of new sales every year to live up to this expectation, something we'll never even come close to you despite the bumper crop of approvals we've seen over the last couple of years. Of hype, narrative based economics and irrational exuberance subside over time, We'll find that we're left with only 2 types of entity. 1, large entities that can't chase science to where science is most interesting and where clinical unmet need is highest. Or in another corner, small biotechs that have single assets that are never built to scale, Cannot scale and are too small to be acquired. So how do we create a corporate structure that can sustainably and scalably after the problem of genetic medicine and take advantage of all of this innovation that I just spoke about.
In my opinion, you have to consider 2 criteria and blend them together. The first criteria is one that I call scale and focus. Interestingly, in the biopharmaceutical industry, what wins early is not wins late in terms of scale. What wins early is what we call diseconomies of scale, meaning focus at the level of each biology, focus the level of each disease. Small groups of scientists that are highly incented to just get all problem right tend to dramatically outperform large pharmaceutical companies going after that very same problem.
But as their programs evolve and move into late stage development and the commercial ecosystem. What one finds is that economies of scale, consolidation and shared learnings become vitally important to the prosecution of
those programs. So criteria number 1
suggests that communication of those programs. So criteria number 1 suggests that we need to solve for focus early and scale late, all in the confines of one company. The second criteria is easier to speak about, but just as difficult to solve for. It suggests that every program that you bring into your ecosystem must at once be NPV positive and have a high probability of technical success. NPV positivity makes you a sustainable company over time.
And the high probability of technical success makes you an engineering company and not a speculative company. How do you actually solve for each one of these elements? In terms of NPV, one must realize that there are very few franchises in the world that are as large s a. Acaramidis with a peak year sales estimate of $5,000,000,000 to $6,000,000,000 In fact, most drugs will sell well less than $500,000,000 in peak year sales. That means one needs to be ruthlessly cost efficient in the prosecution of each one of its drug discovery programs to ensure that each one of your programs is NPV positive.
Science forward and try to figure out a disease to work on based on a scientific platform. But what's much more effective In the creation of a great product is to work from a marketplace backwards. What does this mean? It means that if you're working on a disease that's formally driven by the destabilization of a single protein. Why not restabilize it and preserve that important protein versus knocking it out and potentially generating something that's more unsafe and less effective.
In the confines of a disease where one must chronically dose a child up and until their growth plate closes. Why create a medicine that requires a daily injection versus an oral medicine that could be easily mixed in with their applesauce or another food product and that could potentially provide even greater efficacy. And for a kidney disease that manifest 7 or 8 years after the advent of the diagnosis. Why take a gene therapy approach where the durability is likely not to be all that efficient versus a chronic approach where you're actually drugging all the way and through the most severe of the symptomatology. These are the types of things we think about within BridgeBio.
And unsurprisingly, we've tried to solve for both of these criteria in concert. On this next slide, I show how we solve for criteria number 1 through our affiliate structure that allows for focus at the level of each asset when a program comes in. A small group of scientists will work on a disease. But as that program evolves and moves into the clinic and ultimately into the marketplace, it's housed under a single umbrella of commercial activities that allows the application of economies of scale and shared learnings. We solve for the second criteria within our ecosystem Through a focus on the right tool for a specific disease, and we have a large toolkit of some 4 going to 5 modalities, And we marry that with ruthless application of cost and time efficiency so that we can get to IND Oftentimes, dollars 10,000,000 or less for our small molecule programs.
All of this is enlivened by a group of some 400 of my colleagues that are constantly working to generate novel medicines as quickly and efficiently as possible. So what's possible if this BridgeBio experiment works, if we're able to combine these two criteria with this novel corporate structure and the first two ingredients of high patient unmet need and novel innovation. We believe through some luck and some skill that we're on the precipice of creating a genetic medicines company, the likes of which we haven't seen before. Consider the 2 archetypes that we have seen. On the one hand, Alexion and Vertex with blockbuster franchises akin to our ATTR franchise, but with a very limited pipeline.
And on the other hand, companies with smaller products, but very busy pipelines like BioMarin, Sobe, Ultragenyx and others. We have the opportunity for the first time to blend these 2 archetypes together to create a world leading genetic medicines company, one that's going to be around for a very long time serving patients with genetic disease. Now this is a tall order. What gives us hope that we can actually do this? Consider first the productivity of this team over the course of the last scant 6 years.
There are many numbers on this page, and I'll point to just 2. 1st is the 2 approved products that we've generated over the course of 6 years. The second, 15 INDs that we've delivered over the course of a little less than 6 years. On the right hand side of this slide, you can see some of the data associated with the efficient prosecution of our programs, in some cases, taking programs from hit the lead through proof of concept in less than $50,000,000 and in less than 3 years. Consider also the growth of our product platform or what we call a platform of platforms from Discover, where we've added new technologies, new capabilities in statistical genetics and new databases to create Where we've enlarged a number of modalities that we're working on and the number of technologies we're bringing to bear in drug discovery, including things like cryo EM, including things like NMR and including things like molecular dynamic modeling.
Consider our test platform where we have now 20 ongoing clinical trials. Not only are we getting better at clinical operations, we're getting better at decentralizing our trials so we can take the experiment To the patients in need, and we're getting better at using cutting edge statistics such as Bayesian analyses so that we might better design and interpret the data that we're getting out of our clinical trials. And then finally, our deliver platform, which is just starting to grow, And a 100% access as quickly as possible worldwide to our medicines. Consider also the leadership of this company. This Page has basically been unchanged for the last 6 years, suggesting the longevity of vision that many of these very experienced R and D practitioners have, With some 250 scientists sitting underneath them, all entirely focused on the efficient prosecution of new medicines within genetic disease.
And consider finally the most important fingerprint of hope in my mind, which is the 34 programs that we've generated to date, some late stage, some early stage, all targeting well described diseases at their source, all representing a first or best in class solution. Many of these programs you'll hear about today. And since we're from California, I'll take you to the beach where we're surfing waves of genetic and genomic innovation Toward the shore of patient unmet need. I'll suggest that the first wave has actually already landed on the beach. Representing MOCD Type A and second line cholangiocarcinoma, this was a small wave, certainly in investors' minds, but an important wave for us.
Number 1, we got to serve patients with high unmet need. Number 2, we got to take a series of learnings that we can then apply to the next wave coming in heavy, Very close to the beach, representing in and itself, in and of itself, are 4 key catalysts in ATTR, ADH1, achondroplasia, and congenital adrenal hyperplasia. These catalysts alone delivering data in the next 12 months, either proof of concept or phase 3 data represent One of the most exciting pipelines in biotechnology today. But there's actually a 3rd wave right behind it already in the clinic of some 6 Mendelian programs, coupled with 2 oncology programs, we will also be delivering proof of concept data in the next 12 to 18 months. And then further offshore, there's a 4th wave where we're we're working on some of the most important problems, not only in genetic medicine, but in medicine altogether.
KRAS driven cancers, ALS, autism, cystic fibrosis, alpha-one antitrypsin deficiency. You'll hear about a lot of this exciting science Later today. But altogether, we believe we found the right spot at the beach. We have the right corporate structure, and we aim to be here serving patients for a very long time to come. What are you going to hear about today?
You're going to hear about some of our wave 2 programs in our precision cardiorenal presentations helmed by Cameron Jonathan and Mary Scott. You'll hear a little bit more about our gene therapy units, which are wave 2 and wave 3 from Eric David. You'll hear about our Mendelian programs that are wave 3 from our chief scientific officer, Uma Sinha. And then you'll hear about some of the very exciting wave 4 efforts ongoing. First, the RaaS program from Eli Wallace.
And finally, from my mentor, Charles Homsie, you'll hear about some of the exciting activities ongoing in a startup within a startup, which is BridgeBioX focused on new technologies and big unmet need diseases. Thank you for joining us today. I hope you enjoy the presentations.
Thank you so much, Neil. I'd now like to turn it over to our chief strategy officer, Cameron Turtle.
Thanks, Grace, and thanks, everyone, for joining this morning. We'll start the review of our R and D pipeline by looking at a few programs in our cardiorenal division. This is a therapeutic area where we continue to see substantial opportunity given that the unmet need in cardiovascular disease is vast, With it still being the leading cause of death both in the US and globally. And second, we've seen a substantial improvement in our understanding of these diseases over the last couple decades, both on a mechanistic point of view and from a genetic basis. In cardiac disease in particular, What we're moving from is an understanding and diagnosis of disease based largely on how patients present in the clinic by their phenotype.
On the left, we show a rough segmentation of the heart failure population based on their ejection fraction, either patients with HFREF or heart failure with reduced ejection fraction or HFEF, heart failure with preserved ejection fraction. And these categorizations are Somewhat helpful in understanding whether the heart failure is caused by reduced contractility or impaired relaxation, But really, they do very little to help us understand what the mechanistic pathophysiology is of these diseases and an ability to target the disease at its source. Fact, there are probably dozens of causes of diseases for both HFpEF and HFREF causing confusion in terms of what the appropriate therapeutic mechanism is for each individual patient. A way that we're seeing that is an improved way to identify patients with heart failure Is thinking about their disease based on the mechanism at which it presents as well as the genetic associations that cause that disease. Quite a bit about amyloid as a cause of heart failure today, but we're equally excited about data that we've seen in contractile cardiomyopathies as well, Which are caused by mutations in a variety of proteins in the contractile sarcomere, including myosin, troponin, or myosin binding protein c.
In addition to structural or signaling proteins such as TITAN, LAMP2, or BAG3. And we're excited about this transition from phenotypic diagnosis to mechanistic diagnosis because this allows us to identify therapies that we believe are more likely to have a larger treatment effect size. And this has been observed in recent years as we've seen that historically in large cardiovascular trials in the in the left hand side here, We see that ACE inhibitors and ARBs, 2 of the most successful and broadly used cardiology drugs, in a study of over 160,000 patients, Delivered a reduction in mortality of only about 5%. In contrast, in a recent study of a TTR stabilizer In patients with ATTR cardiomyopathy, the improvement observed in these patients was a 30% reduction in mortality over just two and a half years. Perhaps more important from a clinical perspective, in the case of RAS inhibitors, the number is usually between 70a100 in terms of the number of patients we need to treat in order to save a life.
In the case of a TTR stabilizer, that number was approximately 7a half. On the right hand side of this page, you see that another type of genetic data that we use for developing drugs in this cardiorenal division. And this is genetic risk in broader types of cardiology diseases, non Mendelian diseases. And this is a publication by Regeneron and academic colleagues Showing that their PCSK9 inhibitor was dramatically more effective in individuals with high genetic risk than those With low genetic risk for acute coronary syndrome. And these types of broad genetic risk data help us to identify both new targets to potentially benefit patients with these common diseases.
But in addition, they help us select patients who are more likely to benefit from the therapies that are already available. As well as a subset of broader cardiology or cardiorenal diseases, where this mechanism could be appropriate as well. First, we'll hear from our chief medical officer for the cardiorenal division, doctor Jonathan Fox, who will talk about the development of akaramidis for ATTR amyloidosis, Which is a program where we expect to share phase 3 top line data before the end of the year. 2nd, we'll hear from doctor Mary Scott Roberts, who's our clinical lead for the development of Incalaret for the treatment of ADH1, and she'll share updated Phase 2 data from our ongoing study. And lastly, we'll hear from doctor Uma Sinha who will share for the first time clinical data from our GO inhibitor for the treatment of hyperoxaluria.
So with that, I'll turn it over to doctor Jonathan Fox to get started on Akarambitis.
Good morning, ladies and gentlemen. Thank you, Cameron, for that kind introduction. My name is Jonathan Fox, as you've been told, and here's one of the programs that I'm involved in, Akaramidis, For transthyretin amyloidosis. Transthyretin amyloidosis has a prevalence of about 400,000 patients worldwide. And the pathophysiology is that of a systemic disease that involves many organs and tissues, but most commonly presents as either cardiomyopathy causing heart failure or peripheral neuropathy causing both sensory motor and autonomic nerve failure.
It has many genetic drivers within the TTR gene that destabilize the protein leading to amyloid accumulation. So it is a disease of destabilization. The therapeutic hypothesis that we are testing is that a stabilizer Of the gene product that is designed to mimic the protective t 119m mutation that has been found in nature should lead to positive clinical outcomes. The design criteria for optimal therapy in our view, therefore, is that near complete stabilization of TTR will preserve the TTR tetramer and prevent or delay the progression of disease, and that oral dosing with a stabilizer molecule is an optimal means of therapy. As I mentioned, ATTR is a systemic disease with multiple manifestations.
Here, you see a figure of a human body with several of the tissues and organs that are involved. But again, as I mentioned, the most devastating consequences of this disease process Are the cardiomyopathy or ATTR wild type or variant, Centimeters, which is involved with the deposition of wild type or variant, For example, the v122i variant TTR amyloid in the heart leading to predominantly systolic and diastolic heart failure. It likely affects over 400,000 people worldwide with the majority undiagnosed, although this is improving. It typically has a late age of onset after age 50 and is both a progressive and fatal disease with a median survival of 3 to 5 years from diagnosis. The polyneuropathy associated with ATTR or ATTR PN affects about 10,000 people worldwide, primarily in Europe and Japan.
It is exclusively caused by variant TTR. For example, the v 30 m variant found endemically in areas of Portugal, Sweden, and Japan. The onset is between the ages of 30 50, which is also progressive and fatal with a median survival of 5 to 10 years from diagnosis. We are now seeing a rapid increase in patient finding and case finding driven by a noninvasive diagnostic technique that was developed over the last decade. On the left hand side of the slide, you see a time line of the rate of diagnosis in terms of the number of patients diagnosed with the disease And then later, with a more specific and more sensitive technology related to technetium bone scanning, Has shown that in patients who are suspected to have ATTR cardiomyopathy, the diagnosis rate has skyrocketed and continues to grow Now that we have a noninvasive diagnostic technique that has largely replaced invasive heart biopsy for making the diagnosis.
If we take a look at why TTR is important and why the pathophysiology of the disease The protein is produced by the liver. It is secreted into the bloodstream as a 4 part or tetrameric protein that is made up of identical subunits. That TTR tetramer is transported in the blood where it can carry thyroid hormone and vitamin a And it's otherwise cleared by normal mechanisms of clearance of plasma proteins. However, in susceptible individuals, those who carry disease causing variants or who are subjected to some ill defined processes associated with aging, that normal cycle produces a side bar or a leaky pipe of monomeric TTR, which can misfold, aggregate, and be deposited in tissues and organs as amyloid. If we look at this as more of a cartoon, there are 2 ways to stop a leaky pipe.
You can either shut down the entire water line at the original SOURCE, that is the liver, which is targeting the disease upstream, but it deprives the body of the normal functions of TTR, which may be important. The other approach which we have taken is to fix the leak or target the source by stabilizing the destabilized tetrameric protein, Preserving its normal functions. If we look at this also in this schematic, the disease mechanism shown here involves the native TTR tetramer circulating the blood and under the influence of either the destabilizing variants Or the processes as aging dissociates into monomers, which then aggregate and can be deposited in tissues in a pathologic way. We know that people who carry the t 119m variant are protected from the disease, and this was shown originally in Portugal where members of families carrying the v 30 m disease causing variant seemed to be protected from the disease, and they were found to carry one copy of the variant of the disease causing variant and one copy of the disease protective variant, which protected them from becoming ill. So if we can mimic this mechanism by adding a stabilizer molecule like Akaramidus, if this was designed to mimic the protective variant By stabilizing the tetramer to slow or halt disease progression.
We know from genetic studies in families carrying disease causing variants That the more unstable the TTR tetramer is under the influence of a disease causing variant, the more severe is the disease, both in terms of penetrance and rate of progression of disease. So for example, the L55 p variant shown in the top row, Carriers of this variant have about 100% penetrance that is the likelihood of developing symptomatic disease, and it's very rapidly progressive. The v122 I or the West African variant, which is found in about 3.4% of black Americans, is about half as stable as the wild type shown in the 3rd row. Finally, the t 119 m protective variant that I mentioned in a previous slide is almost 40 times more stable than the normal wild type protein and protects carriers against TTR even if they carry a disease causing variant. The phase 3 ATTACT study of tafamidis in ATTR cardiomyopathy tested 2 doses of that drug, 20 milligrams 80 milligrams of the myglomine salt versus placebo.
Patients receiving 80 milligrams of tafamidis versus the 20 Exhibited greater TTR stabilization as shown in the graph on the lower left hand side, and this comes from the FDA's review of the new drug application for tafamidis that was submitted for registration. We also know that the benefit of tafamidis 80 milligram Versus 20 milligram in terms of clinical benefit was evident on all cause mortality in an analysis of the ATTRACT study, which combined both the randomized Placebo controlled portion of the study as well as the long term extension, and those data are shown on the right, and that was presented by one of the principal investigators Of that study. In our own laboratories, we've compared the in vitro stabilization of TTR By comparing clinically relevant concentrations of tafamidis and akaramidis. So in this graph, you see 2 concentrations of tafamidis that were tested in this well accepted assay of target occupancy by fluorescent probe exclusion. The 16 micromolar represents the mean trough concentration of tafamidis at the 80 milligram dose.
The 26 micromolar represents The reported peak plasma concentration at that same dose compared with akaramidis 10 micromolar, which is a little bit higher than the trough steady state concentration of Akiramidis that is used in the clinic. This shows that Akiramidis demonstrated near complete TTR stabilization in vitro at these clinically relevant concentrations. Getting on to the clinical data, we performed a phase 2 trial In patients with symptomatic heart failure and ATTR cardiomyopathy, which included both a randomized 28 day portion And a 15 month open label extension that has been previously reported. On the left hand side, you can see a schematic of the phase 2 studies In which in the original randomized placebo controlled study, 49 patients underwent randomization, 17 to placebo, 16 to acaramidis hydrochloride 400 milligram and 16 to acaramidis hydrochloride 800 milligram. Those results have been published in the Journal of American College of Cardiology.
Following the randomized portion of the study, We invited those participants to come into the open label extension. 2 people declined for logistical reasons, and the rest came into the open label extension. 3 had died, 1 had received a heart transplant, and 2 had discontinued for other reasons. So as of the end of August of 2019, 41 patients Continue to participate in the open label extension. The outcomes from this phase 2 study primarily were safety and tolerability.
So we recorded adverse events, clinical events in vital signs, and clinical laboratory parameters. The secondary and exploratory endpoints included pharmacokinetics, pharmacodynamics, including stabilization assays and echocardiographic parameters. Here you see on the left the summary of the safety data from this phase 2 trial. In the placebo arm, 15 people or 88% reported any adverse event. And in the aramidis pooled dose group, there were 21 adverse events.
These were largely mild or moderate in severity. There were serious adverse events, 2 of them in the placebo group and 1 of them in the Akiramidis pooled dose group, And you see those listed in the bottom half of the table on the left. When we looked at ex vivo stabilization, again, as Fluorescent probe exclusion occupancy assay. We had essentially complete stabilization, as a mean plus or minus standard error of the mean at trough throughout the study. This graph shows you the results of serum TTR changes Over the course of the study, in the randomized placebo controlled portion.
In the left one third of this graph, you can see the placebo group, and they essentially were Unchanged over the course of the study. A few decreased, some increased ever so slightly. Whereas in the active dose group, All participants had an increase in their serum TTR, which showed a dose effect, and it also showed that the Patients who carried variant TTR, these patients start out with a lower TTR level before coming into the study Because their TTR is intrinsically less stable than the wild type. And they, of course, as a result of the stabilization across the board, They experienced, proportionately speaking, a larger increase in serum TTR. We looked at the biomarkers and terminal proBNP in troponin I in this study.
And this shows the follow-up in the long term extension, essentially showing that both N terminal proBNP And troponin I remained stable in Akaramanis treated participants throughout the open label extension. Similarly, we looked at a number of echocardiographic parameters throughout the study. And focusing here on a structural Endpoint left ventricular mass and a hemodynamic endpoint left ventricular stroke volume index. Again, we see stabilization of these parameters Throughout the open label extension. Our phase 3 program consists of a single study, The Attribute Centimeters Cardiomyopathy trial.
This embedded phase 3 design includes both a 12 month and a 30 month primary endpoint readout. You can see on the left one third of the slide the key inclusion criteria. Subjects were Eligible to enter the study if they were diagnosed with ATTR cardiomyopathy, either wild type or variant, they had to have Symptomatic heart failure of New York Heart class 1 through 3. And they had to have either an ATTR positive biopsy of the heart Or a positive technetium scan diagnostic with exclusion of light chain amyloidosis by the Standardized serum and plasma criteria. At 12 months of duration of therapy, we will have a readout Of the change in 6 minute walk distance as a primary readout and a change in Kansas City questionnaire as a secondary endpoint, At 12 months in all participants, and then they will all continue on for a total of 30 months duration of treatment, at which point we will do a hierarchical Analysis of all cause mortality and frequency of cardiovascular hospitalization.
Following the 30 month Endpoint participants in the study, if they're still eligible, will be invited to participate in an open label extension. 6 minute walk test was chosen as the readout for the 12 month embedded part of the study as a clinically meaningful treatment responsive endpoint of function. It is a simple submaximal exercise test that assesses aerobic capacity and endurance. It has been demonstrated to measure treatment benefit in heart failure, chronic obstructive pulmonary disease, and pulmonary arterial hypertension. People have also observed that higher rates of mortality observed with lower 6 minute walk distance occurs in multiple cardiopulmonary diseases.
And doctor Matt Moorer of Columbia University has been quoted to say that the 6 minute walk test, a measure of functional capacity, Was identified as a predictor of overall survival in patients with ATTR cardiomyopathy. This shows a summary of the 6 minute walk distance data in ATTR cardiomyopathy and healthy cohorts as demonstrated in the Attract study. So in the graph on the left, you can see that healthy elderly adults who are age matched controls in this Cross study comparison show that on average, people in this age group who are otherwise healthy experience about a 7 meter annual decline in 6 minute walk distance performance. The black line in the middle shows the tafamidis treated group in the ATTRACT study that was compared to the placebo group in the blue line showing a much steeper decline. So the hypothesis behind our 12 month readout is that near complete stabilization of TTR by Akaramidus may slow or halt functional decline in the 6 minute walk distance compared to baseline.
So we have several important upcoming milestones. At the end of 2021, we'll have the acoramitous part a top line data from Attribute Centimeters. Mid 2022, we anticipate filing for registration both in the US by filing an NDA and in the European Medicines Agency filing a Marketing authorization application. And in 2023, as the participants continue through Part B, We'll have the readout of the ACORAMEDIS Part B top line data of all cause mortality and frequency of cardiovascular hospitalization. Thank you very much for your attention this morning.
Now I'd like to introduce doctor Mary Scott Roberts, our medical lead for the Incalorit program, Developing that drug for autosomal dominant hypocalcemia. Doctor Roberts.
Thank you, Jonathan. Audizontal dominant hypocalcemia type 1 or ADH 1 is a condition that impacts approximately 12,000 people in the United States, Such as Alexis and her son, Jackson, pictured here. And while outwardly Alexis and Jackson appear to be quite healthy, we know that ADH can be a debilitating and potentially life threatening condition for the people living with it. Unfortunately, there are no approved therapies for the treatment of ADH 1 and the treatments that are available do not target the underlying cause of the disease. An optimal therapy for this condition would directly target the underlying cause of ADH 1, would lead to resolution of the symptoms and the underlying laboratory abnormalities that these patients have and would be convenient for the patients.
Incalarette is an oral drug that is under investigation with the aim of treating ADH1 at its source. Now we'll dig into a little bit of the ADH 1 disease mechanism in more detail. As its name would suggest, the calcium sensing receptor And the gene that encodes the calcium sensing receptor results in an overactive receptor that's highly sensitive to blood calcium, Essentially, tricking the parathyroid glands and the kidneys into thinking that the blood calcium is normal when it's actually quite low. In other words, in patients with ADH 1, these tissues have an altered set point for blood calcium that is lower than the normal physiologic range. Overactive calcium sensing receptors lead to decreases in parathyroid hormone or PTH secretion, which leads to decreases in blood calcium.
And it's the low blood calciums that cause the clinical symptoms that these patients experience, including hypocalcemic seizures, which often present in infancy, paresthesias, tetanies or severe muscle contractions, which are often incredibly painful, and persistent muscle cramps. The overactive calcium sensing receptor also results in increased loss of calcium in the urine, which is the main cause of the long term complications these patients experience including nephrocalcinosis, which is calcification of the actual kidney tissue itself, nephrolithiasis or kidney stones, found that the median age of ADH 1 diagnosis is 25 years with a range from infancy up to 77 years. And 42% of these patients present with severe symptoms like seizures while 31% present with mild to moderate symptoms. And we know that the degree of ADH 1 symptom severity is directly associated with the blood calcium levels, as you can see in the graph on the left. In dark patients who presented with either no symptoms or with moderate symptoms.
The currently available medical intervention for patients with ADH 1 includes oral calcium supplements and active vitamin d, which is a prescription medication. But unfortunately, these treatments are not very effective in normalizing the underlying laboratory abnormalities or the symptoms that these patients experience as you can see in the graph on the right. Only 22% of individuals had normalized blood calcium and only 29% had normalized urine calcium when on treatment with calcium and active vitamin D. And one thing that's really important to note here is that it's incredibly hard to increase the blood calcium and that results in spilling of the calcium in the urine. And you can see that here in the fact that only 2% of individuals had normalization of both blood and urine calcium when treated with calcium and active vitamin d.
In addition, only 22% of individuals reported improvements and their ADH1 related symptoms and these data suggest that there remains a large unmet need for better treatment options for this patient population. Here we can see the 2 major locations in the body where the calcium sensing receptor does its work, the parathyroid glands and the kidneys. In the parathyroid chief cell, which is schematically represented on the left hand side of the screen, you can see that the calcium sensing receptor detects the extracellular calcium concentration, and it tells the parathyroid cell whether or not to make and release parathyroid hormone into the In ADH 1, the overactive calcium sensing receptor tells the parathyroid gland to go to sleep in the renal tubule again detects the extracellular calcium concentration, and it tells the kidney whether or not to reabsorb calcium from the urine Back into the blood. In ADH1, the overactive calcium sensing receptor results in increased loss of calcium into the urine. And these are the exact locations that Incalaret is expected to act to dial back the activity of those overactive receptors in patients with ADH 1.
And what we expect to see within CALORET treatment is represented on this slide by the light blue arrows. By targeting both the parathyroid glands and the kidneys, Incalaret is expected to increase PTH secretion Resulting in normalization of the corrected blood calcium while simultaneously maintaining a normal urine calcium. And that's exactly what we're trying to demonstrate in our Phase 2 study seen here, which consists of 4 sections. Period 1 is a dose exploration phase in which 6 subjects received the same escalating doses of Incalaret. Period 2 is a dose optimization phase in which the 6 subjects in period 1 plus an additional 7 subjects for a total of 13 underwent individualized and CALORAD dose titration.
One thing to note is that prior to periods 12, all of the subjects discontinued their active vitamin d 1 to 2 days prior to the first Joseph and Calarette and their calcium supplements on the morning of the first dose. Following period 2, patients continue into period 3, which is the outpatient maintenance phase for a total of 24 weeks of treatment, then they can continue on in Calarette treatment in the long term extension. Currently, all of our patients are in period 3 or in the long term extension, and we're planning for a discussion with the FDA Before the end of the year, to review these data as well as to discuss plans for our upcoming Phase 3 study. The key study objectives in the Phase 2 study includes safety and tolerability of Incalaret as well as the effects of Incalaret on both blood and urine calcium as well as parathyroid hormone levels. Additional measures that include a variety of biomarkers of calcium homeostasis are also being assessed in this study.
The goals of Incalarette treatment during periods 12 were quite different. As you can see on the left hand graph, in period 1, all 6 subjects received the same fixed escalating doses of Incalaret with the exception of 1 subject who required a decrease in the evening dose because of a blood calcium that was increasing to the upper end of the normal range. In period 2, on the right hand side, patients were initially started on a 180 milligrams twice daily in line with where we finished dosing in period 1. But then we realized that the optimal Incalarette dose is actually lower for most of the patients, and so we decreased the starting dose to 90 milligrams twice daily. Over the 5 days of period 2, you can see that the mean and Calarette dose decreased.
And by day 5, the dosing range was quite wide with some patients requiring 180 milligrams twice daily while others required 10 milligrams twice daily. These are the baseline characteristics of the study population. 13 participants with a mean age of 39 years and 9 different calcium sensing receptor variants enrolled in the study. All of the patients exhibited the typical laboratory findings that are expected with ADH1, including hypocalcemia, a low PTH, hyperphosphatemia and an elevated or inappropriately normal 24 hour urine calcium. 3 quarters of the participants had nephrocalcinosis on baseline ultrasound, and the electrocardiogram QT interval was prolonged, which is often seen in the setting of hypocalcemia.
Thus far, Incalorit has generally been well tolerated through periods 12 with no serious adverse events reported. Of the adverse events that were reported, most were considered to be mild with one considered to be moderate in severity. The adverse events that were deemed to be related to Incalaret treatment community. Here we can see the individual and main responses on days 15 in the 6 subjects who completed period 1. The day 1 PTH and corrected calcium levels, which are represented by the gray bars, were collected just prior to the first in CALORET dose.
The baseline value for the 24 hour urine calcium was collected at the screening visit. You can see in the graph on the left that on day 5 of Incalarette treatment Presented by the blue bars, all 6 subjects had an increase in their PTH levels into or exceeding the normal range. This led to normalization of the albumin corrected blood calcium in all six participants, while at the same time, all six These figures show the mean pharmacodynamic responses on days 1 through 5 in the 13 participants increased gradually with the mean reaching the lower limit of the normal range by the end of day 2 and maintaining within the normal range through day 5. Concurrently, the 24 hour urine calcium in the bottom panel decreased into the normal range within the first 24 hours of Incalarette treatment and remained within the normal range through day 5. One thing that I'd like to note is that there is a mild increase in the mean 24 hour urine calcium on day 5, And this is likely reflective of the need for ongoing andcalarette dose adjustments as well as the increases in blood calcium.
Similar to what we saw in period 1, the PTH responses to Incalaret were quite robust, increasing from a very low level at baseline well within the normal range within just 30 minutes following the first incalarette dose. The blood phosphate, which you can see in the lower panel, Started at the upper end of the normal range and decreased into the normal range during period 2. In addition, the blood magnesium levels increased from the lower end of the normal range into the mid normal range over the course of period 2 and the prolonged QT interval that was noted on the baseline assessment resolved by day 5 of encalaret treatment. So to summarize, in the 13 patients with encalaret who enrolled in the Phase 2 study, Incalarette treatment led to a normalization in the mean blood calcium while at the same time normalizing the mean 24 hour urine calcium All participants had increases in PTH and decreases in phosphate into the normal range. Incalaret was well tolerated with no serious adverse events reported.
And importantly, these consistent improvements in mineral homeostasis suggest our clinical development program, which includes a conversation with the FDA that we're targeting before the end of the year, Presenting the complete set of data from this Phase 2 study after all of the participants complete the 24 weeks in period 3 As well as the initiation of our Phase 3 registrational study. Thank you for your attention, and I look forward to any questions in the Q and A portion.
Thank you so much, Mary Scott. Next up, we have Eric David, the CEO of BridgeBio Gene Therapy. Eric?
Bridge Biogen Therapy has made tremendous progress since I spoke to you at R and D Day a year ago. We have 2 open INDs, both with fast track designation. We have a robust and growing pipeline of early stage programs, and we continue to build out our internal capabilities in CMC and R and D. I'm thrilled to be able to talk to you today about BVP 818, our AAV program in galactosemia, a disease that many of you already know has significant unmet need. And I'm also thrilled to tell you a little bit more about our early stage pipeline that continues this theme of unmet need and beautiful science with programs in TSC 1 and 2, cystinuria as well as an undisclosed dilated cardiomyopathy.
Now taken together, these programs help offer hope to about 200,000 patients. And we're thrilled to be working with these patient communities, including the TS Alliance and the Galactosemia Foundation. Now some of this work in these newer diseases may also require some novel capsid work. And there, we're very happy to be working with Guangping Gao at UMass with Casey McGuire at Mass General and with Aravinda Sokhan at Duke. And if you look at the entire Bridge Biogen Therapy portfolio It really reflects something very unique about who we are as a gene therapy company and that we remain agnostic to both therapeutic indication and to vector design.
We simply go where great science and unmet need take us. Now for Bridge to be a leader in rare Mendelian diseases, We also have to be a leader in gene therapy because while Bridge remains agnostic to modality, sometimes you're just gonna have to replace the gene. So we've built a fully integrated gene therapy company inside of BridgeBio. We have a lean but deeply experienced team of people drawn from all the gene therapy names that you know and love. We have about 20,000 square feet of dedicated CMC and r and d space in Raleigh, Where we can do all of our research grade manufacturing, our GLP talks manufacturing.
We can do upstream and downstream process development, And we can do upstream and downstream analytical development so that we can hand over to our CDMO partners a fully optimized process That saves us a great deal of money and time on CMC. And we still maintain our dedicated GMP space agreement with Catalent. Since Since we don't have time to cover the full pipeline today, I'm going to focus on these four programs. The high level view is that the CAH and Canavan INDs are both open for enrollment, And we expect to provide clinical updates on these programs in 2022. TMC1, as you'll recall, is a collaboration with doctor Jeff Holt at Boston Children's, A world expert in genetic hearing loss.
Proof of concept has been established in multiple mouse models, and we continue work in mice and NHPs. Galactosemia, which we're announcing for the first time today, is a collaboration with doctor Kent Lai from the University of Utah School of Medicine, currently in IND enabling studies. So now I'll go into a little bit more detail on each of these. Now CAH is one of the largest Mendelian diseases out there. The genetic driver is a 21 hydroxylase loss of function.
Patients are unable to make cortisol and aldosterone, and instead, they make excess amounts of androgens. They require significant doses of synthetic steroids to try to prevent adrenal crisis and to reduce the excess androgens. Now there has been shockingly little innovation in this disease since the development of exogenous steroids in the 19 fifties. These patients still have a 3 to 4 fold higher mortality than their age match controls across all ages. And they have a host of disorders ranging from cardiovascular disease to metabolic disease, bone disease, and short stature.
Not to mention all the problems associated with taking lifelong steroids. Now gene therapy is the only approach that has the potential to allow these patients to make their own cortisol and aldosterone in the right amounts and at the right times. And therefore, it's the only approach that has the potential to get them completely off of steroids or significantly reduce their daily steroid dose. So as a reminder of one of the reasons why we're so excited about this intervention, genotype phenotype correlation studies have shown that if we can give patients just 5 to 10% of native enzyme activity. We can move them from classic CAH to the non classic phenotype, which is largely asymptomatic and often does not require any treatment.
On the right side of the page here, you see the NHP studies we've done where we looked at the amount of protein we're able to induce in the patient's adrenal glands. We found that in the e to the 12 range, we're able to get as high as 9%, So well into that 5 to 10% range. And then dosing in the mid either the 13 range, we are able to get as high as almost 25% of wild type enzyme. Our phase 1, 2 first in human trial is currently open and enrolling patients 18 years and older. We plan to dose across Three dose groups, 3 patients in each group, and we'll escalate based on safety.
We can also expand at any dose needed. Now once we have safety and efficacy Early in the study, we can leverage our fast track status with FDA to talk to them about stepping down the age range. And we anticipate sharing clinical on this program in 2022. For our AAV 9 therapy for Canavan disease, we have the privilege of working with doctor Guangping Gao at UMass. Now all of you know doctor Gao as one of the pioneers of AAV gene therapy, but many of you may not know that he actually cloned the gene for this disease back in 1993.
And you all know how tough it was to clone a gene back in 1993. Now this is an absolutely devastating neurological disease where patients present typically in the 1st 6 to 8 months of life by missing a developmental milestone or in an even more heartbreaking way, Losing a milestone that they had already achieved. The patients often pass away in the 1st 2 decades of life, and they have very little, if any, motor control. They have very poor head control, eye control, and they suffer from seizures and hyperspasticity. So it's just all around a completely devastating disease.
And we designed BBPA 12 as a systemic AAV therapy to get not only into the deep cortical white matter that's so relevant in this disease, but also to treat a variety of other tissues in the body as the ASPA protein is actually expressed in almost every tissue in the body. We're currently enrolling our 1st in human phase 1, phase 2 trial. We're dosing at 2 dose levels, and we can escalate or expand based on safety. Now this is a disease where we'll be able to get some early readouts, on biomarkers, especially NAA, which we can measure by magnetic resonance spectroscopy in the brain. We Also measured in the urine.
We anticipate sharing clinical updates on this program in 2022. I should also mention that we've been running one of the largest natural history studies for Cannivan disease in parallel with this. I wanted to give a quick update on our AV therapy for TMC1 hearing loss, which, as you recall, is a collaboration with doctor Jeff Holt at Boston Children's. Now this is a loss of function in a transmembrane ion channel in inner and outer hair cells, leading to complete bilateral hearing loss in children. For TMC designed to restore natural hearing across a wide range of frequencies.
Now in the cochlea, sound waves move the hair cells back and forth. As the hair cells are displaced, there's an ion flux through the TMC1 transmembrane ion channel. And that ion flux gets collected into the otic nerve And channeled into the brain where we interpret it as sound. Now unlike some other forms of genetic hearing loss, in this one, The hair cells do not degenerate, so we have the opportunity to restore a fully functional transmembrane protein into them. Doctor Holt has developed a knockout mouse for this disease, which is characterized by profound deafness in the early days of life.
You can see in this chart, we're looking at auditory brainstem responses or ABRs. In red at the top, You see the untreated mice, and you see, basically, they are profoundly deaf across the frequency spectrum. For reference, at the bottom, You see in black, the normal wild type mice with hearing across the entire frequency spectrum. And what you see is that in treatment with BBP 815, the mice have recovered hearing to near wild type levels across the frequency spectrum and durable out to 12 weeks. So we're hugely excited by the data we're seeing there.
And this program continues through IND enabling studies now. Type 1 galactosemia or classic galactosemia is caused by a deficiency in galactose 1 phosphate urodyltransferase or GALT. This impacts an estimated 7,000 patients in the US and EU. Now dietary restriction alleviates the life threatening toxicity in infants. But even with the strictest dietary control, patients still develop impaired speech, cognition, and motor function as well as primary ovarian insufficiency due to endogenous galactose production.
In collaboration with doctor Kent Lai at the University of Utah, We developed a BBP 818, an AAV gene therapy to provide the GALT enzyme and restore normal galactose metabolism. Galactosemia is a slowly progressive disease that leads to numerous deficits throughout a patient's lifetime. And patients with classic galactosemia who have less than 1% of Normal enzyme activities have the most severe disease. Now in a study of over 500 of these classic galactosemia patients, 85% of them had CNS deficits, and 80% of them had primary ovarian insufficiency. But patients with just a little over 1% of the GAL enzyme activity had relatively normal ovarian development and significantly lower risk of disease complications.
Now I'm not going to belabor this metabolic pathway slide, But suffice it to say that in patients with dysregulated GALT metabolism, the patients get buildups of gal1p, galactose, and galactitol, Which are all toxic in their own way. And they have a deficit of UDP galactose, which is essential for normal myelination. Genotype phenotype correlation studies has shown that patients with more than 10% of normal GALT activity are asymptomatic. And patients with between 1% 10% have much lower disease related complications. So we've been working with doctor Kent Lai and his GALT knockout mouse.
And we can look not just at blood levels of some of these biomarkers, but we can also look at tissue level GALT activity. And what you see on the right hand of the slide is brain levels of GALT activity. And you see how with the low doses of BBP 818, We can get mice to 20% of GALT activity, so already well above that 10% threshold. And at the higher doses, we can get above 70% of GALT activity. So we're very excited about this data and are progressing this through IND enabling studies in 2022.
And I'll leave you with this final slide that I hope summarizes the key themes from today,
thank you so much, Eric. And now I'd like to introduce Uma Sinha, our chief scientific officer. Uma?
Thank you, Grace. I'll be talking about the 3rd wave of programs. At BridgeBio, we continue to target monogenic diseases that we can treat at this source. This is pretty much the hallmark of our drug development activities, And I will discuss 3 individual programs which are already in the clinic. Some of the work has been done in healthy volunteers, Some of it in patients.
So these are fairly representative examples of what we are doing at BridgeBio. The first program will be on primary hypoxeluria and frequent stone formers. This is part of our cardiorenal portfolio. The second program that I'll talk about is in limb girdle muscular dystrophy 2i in our neurology portfolio. And the 3rd program in our Deb is from our dermatology portfolio.
So let's jump right in into the cardiorenal program. This is in primary hypoxeluria type 1 as our proof of concept indication. This is a fairly rare disease with a prevalence of about 5,000 patients in US and UK. Renal excretion of or filtration of oxalate. This oxalate builds up in the kidney and leads to insoluble salts, mostly calcium oxalate.
And these kidney stone deposits made of the calcium oxalate crystals, they lead to renal impairment and end stage renal disease. Want to remind everyone, this is a bad disease for patients. It's identified in early childhood. As the renal function declines, the disease is no longer limited just to the kidney. The calcium oxalate deposits form in Multiple organs.
This results in severe end organ damage. Again, in this particular approach that we are taking to Primary hypercholera. We're trying to do this using an oral agent, which is different from other therapies currently in the clinic or approved for use. The particular path we are The enzyme AGXT is fully functional, and oxalate does not Build up. However, in patients who have inherited mutations in AGXT, the Glyoxalate builds up.
This being the substrate of oxalate results in formation of kidney stones. So how are we approaching this in terms of targeting the disease pathology? As you can see on the Left side of the slide that by targeting glycolate oxidase, we are treating PH one at its genetic source. So essentially what happens is when GO is inhibited, both in animal models and in humans, the Glyoxylate doesn't build up. The reaction stops at the glycolate stage, and glycolate is safely excreted.
So our approach is targeting the pathophysiology, and we want to reduce oxalate, not just in PH 1, but also in broader clinical indications. So what is the stage of this program? Right now, we are in phase 1, And we are studying the agent in healthy volunteers, both in single dose regimens as well as in multiple dose regimen. As is normal, we are measuring key endpoints of safety and tolerability, PK profile as well as plasma glycolate, the PD measurement I mentioned in the previous slide. The reason plasma glycolate is important is because, obviously, the healthy volunteers do not have the Oxalate crystal phenotype.
So glycolate is essentially our placeholder PD marker to educate us about the Agent. The compound has been very safe and well tolerated. We have a PK profile, Which indicates that we have potential for once daily oral dosing. Want to emphasize the oral dosing component is very important because Other agents do not pursue this pathway. The observed dose dependent increases in plasma glycolate is also a very important feature.
Seeing this is extremely satisfying. One is the dose dependence. So it means The compound is behaving in a predictable manner, and it's also good to see the glycolate increase. This means that we are properly inhibiting GOL. I want to emphasize that we are right now taking glycolic level to a level that has not been reported in the literature or by Any other agent?
So we anticipate getting PH1 data in 2022 as well as the Phase II, III initiation. So what did we learn from this particular proof of concept of targeting potential for Expanding this learning to recurrent stone formers, that's obviously not a rare disease. The prevalence is 1 and a half 1000000 In Europe and in the US, what is already known from the literature as well as from our discussion with key opinion leaders Excess oxalate excreting into the urine is a major risk factor for calcium oxalate stone former in idiopathic Stone Pharmas. So this is likely an opportunity. So we have learned a lot from inhibition of GO in healthy volunteers.
We learn more in PH one patients, and then we can take the lesson and take this to a much broader patient population. This strategy is very reminiscent of ATTR. When the field was just emerging, The early understandings were that individuals, the patients who had inherited mutations in their TTR gene, the variant patients, We had a predisposition to disease pathology. Then the field expanded with the use of TTR stabilizer. In wild type patients, we saw therapeutic benefit.
So this I want to remind everyone this is, again, the tip of the iceberg in this field because subsequently, the ATTR field is now expanding to heart failure with preserved ejection fraction and in patients who have atrial fibrillation. So very similarly, we are anticipating taking our lessons from PH 1 patients and expanding the therapeutic opportunity to frequent stone formers. Let me switch gears to neurology now. The second representative Mendelian disease program that I'll talk about, It's limb girdle muscular dystrophy type 2i. It's a rare disease.
Prevalence is about 7,000 patients in US and UK. The disease pathology involves loss of contractility of muscle tissue, Leading to lack of ability to do routine daily tasks, and gradually, the patients become wheelchair bound. There's some other Drug development activity in the field. However, I want to emphasize that we are the only company which is pursuing an oral drug That targets LGMD2I in the clinic. Now we recently we had some very exciting news.
FDA gave us a fast track designation earlier this month. So we are all set to pursue this hypothesis of Attacking the disease at its core. So where exactly is this program now? I want to remind you that the agent that we are studying is ribbitol, which is a naturally occurring compound, and it's being investigated Both in healthy volunteers and in patients. So what is the disease pathology here?
The disease is caused by partial loss of function of the fucuten related protein. What this does is the Fully glycosylated Alpha DG essentially is like a shock absorber. So when Alpha DG is not fully Glycosylated, there is muscle breakdown. Our approach in this particular field is trying to supplement the suboptimal enzyme activity in these patients by providing the enzyme with Supraphysiology levels of the substrate. So we are providing ribbitol, which in turn will get converted to CDP ribbitol, and we see this as a potential to rev up residual FKRP enzyme activity And take the target protein alpha DG to its fully glycosylated form.
Want to talk a little bit about the Phase 1 and Phase 2 data. The Phase 1 healthy volunteer data shows a very safe and well tolerated agent. We have studied the compound in both single ascending dose as well as Multiple ascending dose. As you can see from the graph on the slide, the agent has shown dose dependent exposure in both Single dose and multiple dose regimens. And this property, a very desirable one, has shown that we can predict exposure All the way up to a total daily dose of 18 gram, which is a rather large amount by any measure.
So the healthy volunteer data was very helpful in informing the initial doses of the phase 2 study, which we have Started in LGMD2I patients. The data we'll be reading out in 2022. We're also anticipating presenting data at Muscular Dystrophy Conference early in 2022. So what will we be pursuing in the patients? We're obviously going to be looking at safety and tolerability.
There are functional clinical assessments which neurologists normally do to assess progress or deterioration in these patients, so we'll be measuring that. We'll be measuring the all important PD marker, which is alpha DG, To ensure that protein is moving past the hypoglycosylation and is getting to the optimally glycosylated stage, We're also measuring a very interesting marker, CK. Serum creatine kinase levels are a measure of muscle degradation. Some in the audience may be familiar with this from other muscular dystrophy programs. We are monitoring this very closely in phase 2 patients.
And this data in turn will be informing our Phase 3 dose selection. So in summary of the Phase 2 data, which is emerging now, we'll have safety tolerability, we'll have functional endpoints, The PD marker as well as CK. Let me speak now about the 3rd representative program that we chose to discuss today. Recessive dystrophic epidermolysis bullosa is a fairly rare disease. The prevalence is about 2,000 patients in US and EU.
This is a devastating blistering disease. Even though the disease pathology is very easily identified by the terrible wounds and blisters in the patients, Patients often have nutritional deficit. They fail to thrive and have deformity of hand and feet. It's only recently that the systemic nature of the disease has been fully appreciated. Currently available treatment of DB, As well as the some ongoing drug development, they're all palliative in effort and do not address the systemic nature.
Our program is the only systemic therapy which is in the clinic. Let's talk a little bit about the emerging data and also our therapeutic approach. This particular disease And RDEB is caused by mutations in collagen 7. In healthy humans, collagen 7 works essentially as a anchoring structural protein, And it holds the epidermis and the dermis together in healthy skin. In patients with the genetic mutation, They have modifications in their alpha chain for collagen 7.
So essentially, they cannot Hold the epidermis and dermis together. How is our approach targeting the disease at its source? We are essentially trying to do protein replacement therapy by providing recombinant protein So that it can get to its target source and do the modification. We have already taken this program to phase 1 and shown a well tolerated profile. The dose dependent increase in C7 has been particularly gratifying, and that's Because c 7 is a rather large protein, so it was good to see that it's actually reaching its target.
We have these elevations in collagen 7 deposition. We have followed them by immunfluorescence staining In biopsy samples, the C7 is actually reaching the dermal epidermal junction, so The intended target site of action is being occupied. Phase 2 is currently ongoing, and we Anticipate presenting data early next year. In the patient study, we're looking to show an impact on wound healing, The deposition of C7 in skin biopsy and establishing it's getting to its target protein and, of course, safety and tolerability. In summary, I want to emphasize that at BridgeBio, we have a very exciting Mendelian pipeline.
All of these programs are targeting genetic diseases at their source. In our in my presentation, I've highlighted 3 of our wave 3 programs, which represent our current thinking and our robust pipeline. The first program of the Mendelian Sequence has already been approved. We have FDA approval in molybdenum cofactor deficiency type A. There are 5 mid and late stage programs which are bringing up the rear.
We have ATTR, echondroplasia, ADH1, RDEB and LGMD2I. There are 3 earliest clinical programs which are currently in Early studies in healthy volunteers are in patients, and there are also additional preclinical programs which are bringing up the rear. So I want to highlight that I talked about 3 of our wave 3 programs, but there's a lot of other things happening this year. The acoramidis program and ATTR will be reporting its Part A Phase 3 readout by the end of this year. And soon after in 2022, we will have data in achondroplasia, RDEB, LGMD 2I as well as PH1.
Thank you.
Thank you so much, Uma. And now I'd like to turn it over to Eli Wallace, our chief scientific officer for oncology at BridgeBio.
Thank you, Grace. We have a broad oncology pipeline that includes approved agent and a potential 1st in class research programs. Our FTFR inhibitor to Celtic was approved in May of this year for the treatment of cholangiocarcinoma. This was our first oncology approval And was an important milestone, most importantly for patients, but also because it demonstrated BridgeBio's Oncology's clinical development capabilities. We continue to evaluate TRUCELLTIC in underserved patients, including 3 Phase 3 studies in first line glangiocarcinoma and in gastric cancer.
Today, I'll focus my presentation on 2 of our RAS research programs and BPP398, our clinical stage SHP2 inhibitor. RAS is the most frequently mutated oncogene implicated in approximately 30% of all cancers. As such, the importance of inhibiting this oncogenic function cannot be understated. We have multiple approaches to target RASK driven cancers. The three approaches highlighted here are all in lead optimization and all are structure based design programs where the optimization is aided by inhibitor protein crystal structures and molecular dynamics simulations.
Our G12D project is targeting a selective orally active inhibitor that binds directly to KRAS G12D, the most prevalent KRAS mutation in cancer. Our 2 other RAS programs for which I will provide an update today Are both positioned to be potentially 1st in class. 1 is a G12C inhibitor project where our inhibitors bind directly to both the active GTP bound and inactive GDP bound states of KRAS G12C. Interaction plays an important role in oncogenesis, but little to no role in normal cell function. We anticipate that this approach will provide antitumor efficacy without inhibition of glucose homeostasis in normal cells.
The progress we've made to date and our continued success has been and will be a direct result of highly productive collaborations with both The National RAS Initiative at Frederick National Labs and Lawrence Livermore National Laboratories. These partners bring cutting edge structural biology, biophysics, biochemistry and molecular dynamics simulations to our programs. Our researchers at BridgeBio that have contributed to multiple oncology drug approvals work closely with these leading scientists from both institutions to drive our programs forward. Repeat the patients suffering from KRAS G12C cancer compared to inhibitors that block only the inactive form. 1st, our inhibitors block the active effector binding form of KRAS G12C, which should result in more pronounced and faster inhibition of oncogenic signaling.
2nd, by strongly and rapidly inactivating both the active GDP P bound and inactive GTP bound forms of KRAS G12C. We anticipate greater and faster cell death And as a result, less susceptibility to development of resistance. Using iterative structure based design, we have discovered multiple series of dual KRAS G12C activeinactive state inhibitors. As shown in the table, our KRAS G12C inhibitors rapidly and completely modify KRAS G12C in both the active tp bound and inactive GDP bound states. In contrast, neither Amgen 510 nor Mirati 84 9 can modify the active GDP bound state of KRAS G12 c at all.
Our rapid and complete modification of the active TP bound state of KRAS G12C translates to potent inhibition of RAF effector binding to KRAS G12C. As KRAS G12C only activates effectors in the active state, neither the Amgen nor Mirati inhibitor can block RAF effector binding. Additionally, our inhibitors are significantly more potent at blocking oncogenic signaling in the h 358 lung cancer cell line, then the KRAS G12C inactive state inhibitors. Our KRAS G12C dual inhibitors can block oncogenic signaling in the cellular context as shown in this KRAS G12C a59 gs double mutant cell line, which locks KRAS in its active GDP state by completely blocking GTP hydrolysis. One can see a gel shift at all concentrations of our inhibitor indicating protein modification of KRAS.
As a result, our inhibitor blocks downstream signaling, including phospho MEK, phospho ERK and phospho AKT. As Amgen 510 only binds and inhibits the inactive GDP bound state of KRAS G12C, it has no activity. These data clearly demonstrate that our inhibitors ability to block active KRAS G12C oncogenic signaling, which all of the GDP only inhibitors cannot do. In a KRAS G12C mutant colorectal cancer cell line, Our dual inhibitors are more rapidly and completely inhibit phospho ERK and phospho AKT and have more sustained inhibition at 24 hours then G12C OFF inhibitors. We believe this is a direct result of our inhibitors' ability to quickly engage I modify KRAS G12C in both nucleotide binding states.
In other words, unlike GDP state only inhibitors, Our compounds do not depend on nucleotide cycling to reveal the substrate. In a clonogenic cell assay that measures cell colony formation over several days. Our inhibitors are more potent and retain potency over time. In contrast, GDP state only inhibitors from Amgen and Mirati lose significant activity, such that while at day 6, BridgeBio's dual KRAS G12C inhibitors are approximately 5 times more potent than the competitors. By day 34, our inhibitors are greater than 30 and a 100 times more potent.
The ability of our dual inhibitors to retain activity may suggest that by targeting both states of mutant KRAS, our inhibitors reduce or delay development of resistance. Our lead dual inhibitors have now moved in vivo where they dose dependently inhibit phospho ERK in the MIA PACCARAS G12C mutant cell line. And a single dose leads to sustained inhibition of phospho ERK through 48 hours, the last time point taken. Our leader inhibitors have now moved into efficacy studies where we are seeing rapid regression of established tumors. In this study, once daily oral treatment with 1 of our inhibitors at 30 mgs per kg results in rapid regression of established MIA packet tumors And is well tolerated.
The 2nd research program Iowa Highway today is our PI3K alpha RAS protein protein interaction inhibitor, what we refer to as our PI3K alpha breakers. This program also fits with our strategy of targeting Drivers in oncology. PI3 ks alpha is the 2nd most frequently mutated oncogene behind only RAS, making effective targeting of PI3 ks alpha of the utmost importance. As is well documented, there are 2 primary means of activating PI3K alpha. In normal and tumor cells, PA3K alpha can be activated through growth factor receptor tyrosine kinase mediated direct activation.
Our approach inhibits RAS mediated activation of PI3K alpha can also be activated through direct binding interaction with RAS. Our approach inhibits RAS mediated activation of PI3K alpha, specifically in tumor cells. In contrast, as illustrated here with alpelasib, PI3K alpha kinase inhibitors block AKT signaling in both normal and tumor cells. The targeting of PI3K alpha indiscriminately, however, results in significant issues. As in normal tissues, the PI3K alpha AKT pathway is critical for glucose insulin homeostasis.
As a result, PI3K alpha kinase inhibitor treatment leads to metabolic dysregulation. For example, Greater than 60% of patients in Alpelasiv's pivotal Phase III trial experienced hyperglycemia, with a third of patients experiencing Grade III hyperglycemia. In addition, the compensatory increase in insulin secretion has been postulated to drive treatment resistance by increasing the flux in the pathway. Our novel approach should avoid both hyperglycemia and insulin driven resistance By specifically targeting tumor cells. Thus, our approach may provide patients with RAS, PA3K alpha, At RTK driven cancers, a novel therapeutic option, both at monotherapy and in combination.
Validation of our PI3K alpha RAS breaker approach comes from genetic studies in mice with 2 point mutations in the RAS binding domain. These mutations block RAS's ability to bind and activate API 3 ks alpha. When studied In both KRAS and EGFR mutant lung cancer models, these RBD mutants significantly block tumor growth. Importantly, RBD mutant mice have normal glucose metabolism. These studies provide support for our approach both in terms of efficacy and tolerability.
Our structure based design approach has generated several potent and selective PI3alpha breakers as shown in the table compared to PI3K kinase inhibitor alpelasib. Importantly, inhibitors bind selectively to PI3K alpha, do not bind to RAS, do not affect PI3K alpha kinase activity and are agnostic to the RAS isoform involved in activation of PI3K alpha. PI3K alpha has been demonstrated be activated by insulin receptor substrate compared to a cell line where PI3K alpha activation is dependent on RAS. Whereas our PI3K alpha breaker only inhibits phosphorylation of AKT in the RAS dependent cell arm. These data suggest that our PI3K alpha breakers may avoid the on target hyperglycemia associated with PI3K alpha kinase inhibitors.
Let's now move to BPP398, our potent selective orally bioavailable allosteric SHP2 inhibitor that we believe has the potential to be best in class. Our belief is based upon a predicted pharmacokinetic profile that we anticipate will result in tolerable once daily dosing schedule that may enable optimal safety and efficacy in combination. I refer you to our presentation at the recent AACR NCI URTC Molecular Targets in Cancer Therapeutics meeting For details on BBP 398's preclinical characterization. As has been well described, SHP2 is a non receptor phosphatase that promotes cancer cell growth and differentiation through activation of the oncogenic MAP kinase singling transduction pathway. SHIP 2's position as a central node downstream of receptor tyrosine kinases and upstream of RAS and its involvement in T cell exhaustion Make its inhibition an ideal mode of action for combination therapy.
BPP398 was designed and optimized in collaboration with the research team at MD Anderson with a profile we believe will enable safe and effective combination therapy. It's predicted high oral bioavailability and 10 to Now our human half life should support once daily dosing. Based on strong preclinical data, we have prioritized 3 combinations with g 12 c inhibitor, EGFR inhibitor, and anti PD-one antibody nivolumab. These last two combination studies will be conducted in collaboration with our partners, Liam Bio and BMS, respectively. Preclinical mouth efficacy studies with BPP398 have significant antitumor activity in multiple models with maximum efficacy achieved with 100 mg per kg once daily dosing.
For example, in this dose response study in an EGFR driven lung cancer model, BBP 398 treatment results in tumor regressions. In multiple preclinical studies, maximum efficacy is achieved with exposures that are above IC50 determined from tumor pharmacodynamic studies for approximately 15 to 20 hours a day. Predicted Clinical Pharmacokinetics estimate that efficacious levels can be achieved with once daily dosing While also allowing pathway recovery in the case that it is required for tolerability and combination studies. BBP 398 is currently in a dose escalation phase 1 in advanced cancer patients with map k pathway alterations. To date, BPP398 has behaved as expected with observed pharmacokinetics and pharmacodynamics in line with predictions.
We will explore 4 monotherapy dose expansions at the recommended phase 2 dose and initiate combination studies next year. In summary, we have demonstrated our ability to develop precision oncology agents with the approval of TrueCeltic. And we have a promising pipeline of programs Falling close behind, including our novel KRAS G12C dual GTP, GDP inhibitor and our PI3Kalpha RAS breaker efforts as well as our differentiated SHP2 inhibitor, BPP398. As we look forward to a productive 2022, We anticipate identification of a RAS development candidate, presentation of BBP 398 Phase 1 clinical data, and initiation of BBP 398 combination studies. Thank you.
Thank you so much, Eli. And now I'd like to welcome Charles Holmesy, Chairman of Pharmaceuticals at BridgeBio.
Good morning, everyone. It's my job as part of R and D Day to tell you a little bit about BridgeBio X. As most of you know, BridgeBio was founded around the concept of Mendelian diseases where a single gene contributes the entire phenotype. Disease essentially or all the complications of high cholesterol, coronary artery disease, etcetera. What is going to be new for BridgeBio, is this effort, BridgeBioX, where we're going to look at more complicated genetic space.
10% and maybe even less. So we're gonna are those diseases where a single locus, if we target them with a drug, will have an important impact so called polygenic disease. So don't think of this as a qualitative difference from what we've been doing in the past Where we focused on Mendelian disease, where we often worked with academics who had already started a therapeutic effort. To interrogate large databases and find genes that likely contribute in a causal manner to polygenic diseases. So what do we need to do that?
We need to build capabilities. We already have, as I alluded to, a statistical and computational Genetics group that has been doing a great job, and they're gonna even ratchet it up a notch. We also need to build a serious, from the beginning drug discovery effort, which will include things like protein expression, high High throughput screening, cryo EM, you name it, we need to have it. And most importantly and for the most part, A really wonderful chemistry group, which we already have, but we're all are going to have to add to that. And much of this can be done using outside CROs, contract research organizations, but we really need to have the strategic insight, The understanding of pathophysiology, the translational physicians look at disease on the inside.
And that is all happening within BridgeBioX and its reach into the BridgeBio Organization. So that's kind of a small look at BridgeBio X. It's gonna I guess, the labs are gonna be down on the Stanford campus. So before I end, let me express my heartfelt thanks to all of the BridgeBio employees. You guys have been doing a wonderful job in helping to build a really great company.
I really remarkable effort. At the end of the day, helping patients is just about the best thing in the world. So thank you very much. Really appreciate it. We all do.
Thank you so much, Charles. And now to wrap things up, I want to bring Neel Kumar, our Founder and CEO, back up for some concluding remarks.
We're very privileged to be working with outstanding academics, physicians, patients, and their families. We don't get the chance to thank them enough, But this is a sincere thank you to all of them and a thank you to all of you out there supporting this company as we try to generate the next generation of medicines that matter
I will now turn it over to Cameron Turtle, who is going to be moderating our Q and A. Thank you all.
Thanks, Grace. We'll start the Q and A with Salim Syed from Mizuho.
Great. Great. Can you hear me? Yes. Yes.
Okay, great. Thanks so much for all the color today, guys. Super helpful. First question is actually the most important question for Neil. Neil, can I join you on the beach?
That slide really reminded me of the warm weather in California. It's getting cold here in New York. I had a couple of questions maybe On acryamidis, if I can, and then maybe one on one of the other programs. So Neil, I noticed you mentioned in there Peak year sales for ACRA AM and it's a $5,000,000,000 or $6,000,000,000 which is higher than the $4,000,000,000 that was in the Eidos merger docs. I'm just curious What has changed, if anything, to for that higher number?
And do you prefer I just ask all my questions now or just sort of Okay. And the second question on macaramidis So as we're approaching this Phase III readout here, obviously, the market's not interpreting this trial as risk free. And I presume part of this is because when we look at the 6 minute walk data here from Pfizer, it was never Baseline adjusted for the 80 milligram versus 20 milligram tafamidis. And I think everybody understands that Acarambitis stabilized. It's much more of the tetramer.
But how do you guys get people comfortable here with the curve if we're looking at TTR stabilization on the x axis and 6 minute walk, not mortality on the y axis. As we stabilize more of the tetramer That you will like what should that curve look like? Is it more linear? Or at what point should we expect to see some sort of Plateauing here. How do you get people comfortable with that curve?
And then just maybe on The last question, I'll just ask an in color question. Just given the high degree of variation in dosing there with 10 milligram daily and I think it was 360 milligram daily. Just curious, how you guys are thinking about The strengths that you would need here in the pricing framework, just given the multiple strengths and the titration schedule. Thank you.
Yes, sure. Maybe I'll take the first one and I'll kick it over to Jonathan for the second question and Mary's talk.
For the 360 milligram Just curious how you guys are thinking about the strength that you would need here in the
Okay. I'll just give some background noise. So just in terms of the peak care sales, Selim, I mean, I think what we've been encouraged by is the continued growth of the prescribing base for TAF, both within the US and actually ex US, which has outperformed our expectations. We're up to Some 27,000, claims for ATTR Centimeters, and that number continues to grow exponentially. And if you look at the fiber base, which is a little bit above 1,000.
What you can see is a great number of cardiologists that are really, you know, sort of, not AMC associated cardiologists are picking up this disease. So with that, we're able to refine our numbers up in terms of penetrance Closer to that couple 100000 range, ultimately, which we think is consistent with that 13% to 15% of HFp patients having ATTR Centimeters, which in turn, I think, with some fairly conservative modeling gets us closer to that $5,000,000,000 to $6,000,000,000 Number that we spoke about, and I think we continue to project a best in class profile for within this disease state. So With stabilization on the x axis and 6 minute walk on the lives, just maybe I'll kick it over to Jonathan for some comments there.
Yes. I think maybe the way to think about this it's Jonathan Fox here. The way to think about this is in my presentation, we added a line in the graph there That represents what sort of the natural course of gentle decline in 6 minute walk performance in an otherwise healthy Age matched cohort of about 7 meters per year in people who are in their 7th, 8th decade, so to speak. And so that might represent sort of a best case scenario if we are successful in largely Slowing or even halting progression by turning off the generation of monomers at bend this fold and aggregate and get deposited. And, I mean, our the Phase 2 open label extension data that we presented back in 2019 would in a sort of a Broad strokes, I would say, small numbers in an uncontrolled open label extension, but reassuring in the sense that All the parameters we looked at, the biomarkers, the echo parameters, were stabilized over quite a long time and we'll be looking to provide an update to those Data early next year if the abstract is accepted.
So it's really hard to tease apart what the 20 versus 80 in Attract really Might have done, but it's clear enough from their initial publication that there was a clear separation between the treated and untreated or placebo Allocated participants in that trial that from the get go, which is what drove us to Designed this somewhat innovative approach to having an embedded Part A readout at 12 months.
And then, Marysa, I'd want to handle the ecalorant question.
Sure. So the ecalorant dose titration will be fully outpatient in the phase 3 study with laboratory assessments that'll be performed on a semi regular basis with decreased frequency over time In order to maintain blood calcium in the normal range, and this is similar to other endocrine disorders, for example, hypothyroidism in which patients are treated with Levothyroxine. Adults are started on a relatively similar dose, and then the doses are adjusted on an individualized basis based upon follow-up laboratory values. So the exact dosing schedule will, of course, be determined after our conversation with the end of with the FDA at the end of phase 2 meeting. But but that's where we're thinking at this point.
And so, Wayne, it's probably a bit early for pricing on this The wide range of dosing does create some challenges there. But as we get into the outpatient setting and see where most of the patients end up, then we'll probably have a better answer Okay. Thanks, Salim. Let's move on. Anupam, you want to get going next?
Hey, guys. Thanks so much for taking the question on this R and D Day. Two quick ones from me. So, thinking about ATTRIBUTEM, the results coming, are we going to get a look at CV hospitalizations and mortality Sort of in the adverse event table in 4Q, kind of similar to what we experienced with the Phase 2 OLE results. Or are you guys Stay blinded to those results till 2023.
And if we're going to get some type of look, how are you guys thinking about it in terms of curve separation? And then, Second question. Know the focus in 4Q is on 6 minute walk distance. Should we be thinking about similar baselines relative to what we saw on a track tafamidis, which I think is around 3 50 meters. And if tafamidis showed a 25 meter decline at 12 months, what would be a win scenario for you?
Thanks so
much. Hi, it's Jonathan here. To the first question, I would say that we will I need to provide a summary level data analysis of AEs and SAEs leading to death and total hospitalizations. But in terms of The analysis of all cause mortality is an endpoint and CDH as an endpoint. We will remain blinded to those until the end of Part B.
And to the second one, as I mentioned in my previous answer, I think a best case scenario is if we can halt progression as Reflected by no worse of a decline than in an otherwise healthy age match cohort, that to me is would be a pretty outstanding result. And even if we split the difference between that optimal result and what you saw in ATTRAC At 12 months, I still think that would be a major improvement in clinical benefit.
Yes. Should we go to Ellie next from UBS?
Hey, guys. Thanks so much for taking the communications. And thanks for all the color on the program. Just for TTR again, just can you remind us just how you're thinking about The performance of the placebo arm in your trial compared to tafamidis' placebo arm, just if there could be any differences between those placebo performances across the trials, just like given the changes in diagnosis and I guess different understanding of the disease now versus when Pfizer has started their phase 3. And then also just on TTR, I guess, what could be the potential impacts of COVID, I guess, on the placebo arm,
Hi. It's Jonathan again. So to the first question, I apologize I missed that one on the last go around. In terms of baseline characteristics, very similar to what you saw on the TRACK in terms of baseline biomarkers, Baseline 6 minute walk, a really very similar patient population. But we did put some tweaks into the protocol to try to avoid the Sickest of the sick, and that was on the recommendation of our expert clinical advisory board, many of whom helped design and execute on a track.
So hopefully, that happens across the board in drug development that you learn from the experiences of others if you if they've come before you. In terms of I'm sorry, the next one was Sorry,
the impact of COVID on Oh, right.
Yeah. We were pretty nervous, to be honest with you, in terms of enrollment and getting people in for their visits and such as the pandemic unfolded around the world. We have a lot of patients in places like the UK and Spain and Italy where, you know, as you know, it wasn't just the United States And other countries having a big problem with it. But thankfully, for for whatever reason, we were able to do a lot of telephone visits For routine safety checks and get people in for their 6 minute walks, especially at the critical 12 month time point. So we've been touch wood.
We've been very lucky that the patients have remained totally committed. They haven't sort of hidden away from us and the investigators. A lot of the centers, the research centers are separate from the main hospital. So they were able to take advantage of that physical separation in terms of distancing. And right now, the data collection seems to be going pretty well.
Is there another one?
I think that's it. Jeff, can we go to you from Bank of America?
Can you hear me? Yes.
All right, perfect. So just a couple, another one on aquaramidis. When you look at the data, I'm just trying to reconcile maybe other points of differentiation. When you look at TTR stabilization, how does that correlate in you guys view with patient outcomes? And Do you think that there's an opportunity for more differentiation just in both the cardio versus the neuropathy indications when you look over the totality of the drug.
And then more of a strategy question for Neil. In gene therapy, you guys are obviously committed to the modality. When you think about opportunities, and there's lots of them, for BD, How do you really what is the math on balancing the unmet need with probability of success As you look to further add more assets to the mix.
I think in terms of stabilization and A couple of things have been, I think, well communicate From the genotype phenotype, every time we do worse in terms of stabilization, you see patients in general doing worse if you line up thermodynamic stability versus pathogenicity or age of onset in this disease. In polyneuropathy, I think as you point out, that Flunusol outperforms tafamidis 20, so you can see ever increasing stabilization leading to better clinical outcomes. I think most importantly, in the cardiomyopathic space. You saw 80 mg outperform 20 mg, almost a 20% relative risk reduction in terms of mortality. And so, I mean, there's a broad set of data That suggests every time you do better in terms of stabilization, you should do better for these patients.
And as Jonathan suggested in his earlier comments, you can Kind of weave this connect the dots from mortality back to 6 minute walk data based not only on some of the attract data, but also from the lane Paper where one can connect, you know, hazard ratios to 6 minute walk performance in this patient population. So So I think all of all of that that case has been made. You know, the degree to which the response function is linear, versus something else, I think, is something we'll in in our we're testing, obviously, in this clinical trial. So that's question number 1. I guess question, number 2 On gene therapy strategy, a couple of things inform our our our gene therapy approach.
Obviously, we've been willing to cut across a a a wide variety Oregon's therapeutic areas and use a number of different vectors. But the one thing that we're always looking for Is a threshold like effect in general. You heard about 2 programs today where you're looking to replace, you know, somewhere between 10 to 30% of the wild type enzyme, which is a low bar versus some of the what you see in certainly neurodegenerative diseases where you need to get close to a 100 can't go over, and you can't go too terribly under. So that's one thing we look for. The second thing we look for is a marketplace large enough to warrant The early stage expense, with our small molecule programs, we're typically the IND at under $15,000,000 I think in gene therapy, Especially given the FDA's recent guidance, you're going to be looking at $30,000,000 to $40,000,000 INDs.
And so one needs to be very careful in the selection of the end market so that, you know, the the expense can be justified on a risk adjusted basis. So that's, at least 2 of the criteria that we use. But look, we're we're bullish on, on the ultimate use of gene therapy to address some of these very severe diseases and continue to look to growing that portfolio over time.
Okay. Let's go to Paul next from Goldman.
Hi. Thanks, Neil and team. Congrats on all the progress and for this comprehensive overview. Three questions from us. First on acoramidis and ATTR, so maybe for Jonathan.
I think there's some investor debate on some of the Assays that are used to assess the various agents. You mentioned FPE in your slides as well as other methods. So I was just wondering, can you comment on Just your view on the reliability of these assays, just given the different results that are out there For like 3rd party drugs, like COMT inhibitors, like toplicone and whether like, you can actually accurately replicate physiological conditions and this And this how this translates to predictability of clinical outcomes. Our second question, probably for Mary Anne and Calarette is, will you have 6 months data before year end and before your planned FDA meeting. And do you still think about a 50% reduction in serum calcium as the appropriate endpoint here Or just what your updated thoughts are post your Phase 2 data.
And then third, for Eli on the oncology side with regard to the dual GDP and GTP inhibitor for KRAS. Can you maybe just comment on how you're thinking about potential dosing here? Is QD or possible here? Or is BID Dosing likely. And just given that the Amgen and Mirati drugs require a fair amount of active drug to be dosed each day, Is there going to be a substantial volume here?
And just how do you think about sort of the risk benefit profile with regard to adverse events? Thank you very much.
Hi, it's Jonathan again. With respect to the ex vivo assays, we've used both the FPE, which is a site occupancy assay, as you know, And the Western blot ex vivo stabilization assay kind of in parallel all through the program. And they've given very, very consistent results, Both when spiking drug in vitro and in taking samples from both nonhuman mammals and humans, once we got into the clinic. And even in healthy volunteers, very consistent results that, apiraminis across the entire dosing interval at the dose we took forward into Phase 3 Does result in near complete stabilization. How that relates back to clinical benefit, that's the best experiment we're running down.
We do have tantalizingly reassuring data from the Phase 2 program. But as I mentioned earlier, it's small numbers. OLE, obviously uncontrolled. But if you can extrapolate, if you're bullish like we are, It looks pretty good. With respect to the clinical relevance, those assays, especially when they're run on clinical samples, They're not sort of semi purified or filtered at all.
It's whole serum or whole plasma That's used in those assays. So with respect to the ability of other plasma proteins like albumin to interfere with the interaction of the drug with the target, protein binding for Akkeramidis is rather modest compared to most Most small molecule drugs, including tafamidis, which has very, very high protein binding, so that the free fraction that's available to interact with the target is limited. And Others have published on that, and we've published on that aspect of the pharmacokinetics and pharmacodynamics of the class. With respect to Tolcapone, it's an interesting molecule. It also happens to be TID and hepatotoxic.
So its ability to compete in this space seems quite limited. I I imagine, you know, if there there's probably no real no drug that That I know of that works 100% all the time and 100% of people who get it. So maybe there are a few people out there that might benefit from Tolcapone, but I don't hold it up That's a great option given the current competitive space. In terms of other aspects of stabilization, I think the other thing to keep in mind is If you there's when you look at serum TTR levels, as Neil mentioned, the worse the more destabilizing the mutation, The worst the clinical outcome for people who carry those mutations, higher the penetrance, earlier age of onset, more rapid progression. And they have, in tandem with that, lower steady state TTR levels with otherwise good nutrition and so forth.
We know from our own work that when people are on Akkeramidis, everybody's TTR level goes up into normal range. It doesn't overshoot. It seems to restore what the normal balance might be and all the normal physiological functions of TTR. And so as an in vivo reflection of the pharmacology of the drug in terms of stabilization, serum TTR seems to be a pretty good measure or reflection of that.
Great. We'll turn it to Mary Scott to talk about the INCHALARA data for the end of the year.
Sure. Thanks. For Your question on INTELLARET, we plan to discuss the data that's available from our live phase 2 database with the FDA at the end of phase 2 meeting. And then we'll plan to present the results from the full phase 2 study that includes that 6 month outpatient period early next year. But we do know that the preliminary data shows continuation of the response that you were you saw today during the presentation.
As far as the endpoints go, we think that the same endpoints that we presented for the phase 2 study, blood and urea and urea as well as parathyroid hormone are both clinically meaningful endpoints that could lead to registration of the drug. And we know that these are the parameters that drive both the symptoms that the patients experience as well as the long term complications that are associated with the with the disease.
Thanks, Scott. And Eli, we'll turn it over to you to answer your question.
Thank you. Yes, the way we are thinking about it, The dosing and the coverage that we need is it's still early days, but I think it's important to point out a couple of points. With other covalent inhibitors that don't need to worry about the cycling between active and inactive RAS, they seem not to need to cover as much As the early stage KRAS inhibitors, we that hit actively signaling KRAS as well as the Inactive Forum feel that we're probably going to behave more similarly to those. I mean, it's early days. What I did show in my slides was that the PD effect went out to 48 hours.
That as far as I know from published data that hasn't been shown with other inhibitors. And I will tell you our early xenograft studies. We are outperforming the inactive inhibitors on EC level With once daily dosing quite significantly. So we're optimistic that we're going to be able to cover the target In a meaningful way with once daily dosing, but it's early. And so that's something certainly we're going to be a key component as we optimize our compounds towards Candida.
Thanks, Eli. We'll go to Ram next, if we could, from H. C. Wainwright.
Hi. Thanks for taking my questions. Can you hear me? So, firstly, on acuronidus, I was just wondering if you could, looking ahead To the potential commercial situation, maybe break down for us how you're thinking about the market segmentation between silencers and stabilizers.
Yes. I'm happy to start on that. Know, I think, the first thing that's going to drive market share within this devastating disease is obviously efficacy. Our best understanding of efficacy is it ties back to control of the toxic monomers. And in turn, quantitatively, whoever does best in terms of that control Through knockdown or through stabilization, will be the superior agent.
We think a 95% stabilizer mean max knockdown agent in terms of efficacy, and then ultimately do better, obviously, than a 45% stabilizer, Which is TAF at AEMIG. So that's on the efficacy side. I think on the safety side, The second most important principle in this marketplace will be the preservation of TTR. We know that it's a 20th most abundant protein. No one doesn't have it.
In mouse models, when you eliminate it, you can see relatively severe toxicity. And so if you could do all of the same things but preserve that important protein, why would you not do that? And so, you know, we believe that small molecules for that reason, if they're able to deliver Samer better efficacy will be the preferred tool. As Jonathan mentioned, not everyone is going to respond to to to a single agent, But we think the superior small molecule, if it is able to deliver best in class efficacy, and by virtue of sparing the tetramer will have best in class safety profile, Would be that preferred agent. So whatever whatever, you know, historical comps you use in terms of best in class orphan agent, be it 70% market share, 80% market share, That's the type of market share that we would expect in the event that we're able to deliver the data that we think we could.
I was just going to add a comment. It's Jonathan here. If you go back To the presentation and you see the rapid increase in diagnosis and incidence rates now that we have a well established noninvasive Diagnostic algorithm in place. And there's a lot of excitement in the general cardiology community. It's been pretty frustrating For a lot of heart failure doctors taking care of people with progressive disease with an otherwise unspecified etiology.
And if you can call out the people who Actually have ATTR as the etiology of their heart failure with a specific treatment that can reduce Hospitalization and mortality, as we hope we will be able to demonstrate, then you've really made a pretty major advance. I mean, if you look at some of the other therapies For heart failure, the cardiology community has gotten pretty excited about even a 10% or 12% or 15% relative risk reduction Of morbidity and mortality in this progressive disease class. So we have the opportunity here to really make a quite a big advance. And the excitement is being energized by now that there are, in fact, treatments coming online Thank you. As we go back around this in the not too distant future, there's a lot of excitement about ramping up efforts to identify these patients Who in fact do have amyloid heart disease.
Great. Thanks. The second question is with respect to congenital adrenal hyperplasia. And again, it's, in the market segmentation sort of vein. If you can talk about how you see the landscape developing, assuming there's effective gene therapy alongside, for example, CRF1 receptor modulators and to what extent you expect 1 to Potentially outcompete or elbow out the other versus, you know, with respect specifically to The number of patients on therapy and if cost considerations might play a role in that.
Great. Eric, if you're on the line, would you mind answering that question?
Sure, of course. Yes. No, I think Look, I'll say at the outset, I don't think that there will be patients who take Some of the CRF antagonists who, who well may end up on gene therapy, there may even be room in some patients Given that, you know, as Jonathan said, no patient responds exactly the same as any other patient to to a given drug, you know, there may be patients who end up on on both gene therapy as well as the CRF antagonist. I think the most likely thing is, you know, you're going to see uptake of the CRF antagonist, you know, until the time that gene therapy reaches The broadest marketplace. But when we speak to KOLs, when we speak to patients about this, Everybody sees the CRF antagonist as largely incremental change here.
They yes, you've seen reductions in 17 OHP, you've seen reductions in A 4. They're both in Phase 3s now, and so it remains to be seen whether that translates to any reduction In, you know, the the exogenous steroids that the patients take. But I think the thing that, you know, that The CRF antagonist, even if they show some modest reduction in exogenous steroid use, you know, they cannot allow the body to make Cortisol or Aldosterone. And so gene therapy is the only treatment that offers that potential and therefore the only treatment that offers patients the opportunity to, You know, potentially completely eliminate steroids or very significantly reduce that.
Understood. And then the last question is for doctor Wallace. I just wanted to see if If you could comment on the competitive landscape development in the FGFR inhibitor space, particularly as this pertains to infegratinib. And, specifically, if you could comment on FGFR2 selective specific inhibition approaches in that context And what implications that might have, if any, for the future commercial trajectory of invigratinib? Thanks.
Yes. I'm happy to handle that. Maybe I'll just go back to the comments that Eric just made a moment ago. We're happy to share As well, our projections, I think the bifurcation, as Eric just mentioned, number 1, in terms of efficacy is going to be endogenous cortisol production. And for that, one considers that, that, younger population to be much more the penetrant population versus older, and it breaks out by Gender as well.
So we're going to be probably much more used in the female population versus the male population, especially as you get older and older. So You know, we'll we'll put forth more, projections around that as as we get some more data around the program. With respect to emfogratinib, I think, look, number 1, We were heartened by some of the data that we saw recently, from relay with our FGFR2 specific inhibitor. Overall, as you well know, What was thought to be the limitation in this field is that FGFR1 inhibition in concert with FGFR2 inhibition drove you to your MTD Based on the fact that hyperphosphatemia is arising due to FGFR1 inhibition, I think it remains to be seen thus far as to whether or not you can says those high ORRs, based on FGFR 1 sparing drugs. Certainly, I didn't see anything, in at the recent triple meeting that suggested To me that, the FGFR 1 sparing drugs are able to, lack FGFR 2 and get you to a to a Check like response or or or something like that.
They seem, you know, marginally safer in the ORR at 50%, which will likely trend down To something like 40 or, you know, 40 or less percent is not that far off from what we're delivering in, you know, FGFR to 2nd line, true second line patients between us and and, Insights Drug. It's it's, you know, high twenties The mid thirties in terms of ORR. So I think they're going to need to do better than that. In terms of ORR, my my hope is that they continue to communicate to interrogate that space chemically and, then when we find something that, that that can do that. Otherwise, obviously, there's something more complicated going on in the biology.
If it's truly FGFR2 fusion driven and, you can get to a higher degree of inhibition and yet you're still at ORRs of less than 50%, Something else is going on. So overall market share wise, I mean, it's going to take a while to develop these things. Obviously, they're going to have to come in the resistant population. So I don't think it's going to be a monster market. It's not a monster market for us or Incyte.
And I doubt it will be
a monster market for them either. But, yeah, my hope is that they can do better for patients as an ORR in the mid-30s should be able to be surpassed with a targeted agent.
Thanks, Ram. Tom from BTIG, if you're on and interested in asking a question, we'll go to you next.
Okay. So stay away from AG10. Maybe a question on RDEB for Doctor. Sinha. You talked A lot about systemic
effects.
If your derm penetration isn't spectacular and you're only correcting systemic effects, is it worth pursuing?
And would you
know how to run a trial?
We actually have recently presented data that the protein is indeed getting to the dermal epidermal layer. So that is one of the endpoints we are following in the study. And we can share the poster with you where we show the actual histos. You can see the fluorescently labeling C7 Light light up at those junctions. That is one of the endpoints we'll be following by biopsy.
So both systemic as well as at the site of action.
But
the real excitement would be at the site of action for the drug's efficacy?
Absolutely. That's our early data. Again, this is early days, but we have already seen in the immune histochemistry that the protein is indeed Reaching the dermal epidermal junction.
Okay. Got it. And one quick one for Eli. Your 30 day RAS data is Kind of striking that you're so much better than inhibitors that hit only one state because the cycle time is reasonably fast. Do you have any intuitive thoughts about why it's so much better?
Well, yes, I mean, I think that's something we're Interrogating now, but I think that certainly cancer cells are more perfect Versions of ourselves and are extremely smart and are always trying to adapt and overcome their pressure of inhibition. And if you can do that Simply by expressing the active target, I think you could rapidly generate resistance To an only inactive based inhibitor. And I think that has been a mechanism that has been Postulated by others in the field. So we still need to show that in our own work, but that's certainly a possible explanation for Why hitting both the active and inactive form is able to have such a strong difference over time in that chronogenic assay.
Great. That's perfect. Thank you very much.
I will go next to Greco, who I believe is on for Mani from Leerink.
I have two questions, 1 on Akaramidus and the other on KRAP, and we'll start with Akaramidus. We'd love to get a better sense of the potential impact of the availability of reimbursed tafamidis in different geographies in the context of the Part of attribute, that permits tafamidis. How do you project the risk of this drop out, drop in Driven by tafamidis availability post Part A. And how are you guys positioned for that risk versus
Sorry. Sunny, do you want to
go to
the second question first or should we get started?
Yes. I can go to the second question too. It's on KRAS maybe focusing more on the clinical Although I know it's still early, but how do you see the existing competitive landscape here? And what is the clinical bar that investors Should be applying for success in G12C to be convinced on differentiation here. Thanks.
Hi, it's Jonathan. On Aparamedis, we have designed the study to Account for the availability of Tafamidis, especially in the United States where it was approved and launched right after we started our Phase 3 enrollment. And I think everyone on the call here is familiar with the pharmacoeconomics of the situation in the U. S. At least This is largely a Medicare population.
There is the financial burden on a lot of patients Who can't afford their co pays. And so the people who enrolled in the U. S. Was there was pressure For people only those in that subgroup who couldn't find a way to either pay for it or have it covered To come into our trial. That said, over time, the situation has evolved and people, we have seen some drop ins.
But elsewhere in the world where we enrolled most of the trial, tafamidis is still not widely available or reimbursed, Especially in places like the UK, Spain and Italy. Now we do expect by the time Part B wraps up that that situation will continue to evolve that patients around the world will be able to access Cabanadis through their national health systems or through the Whatever reimbursement mechanisms operate in their region or in their country. But we've accounted for that by modeling what the drop in could look like over time. And two things, risk mitigate against too much of a dilution in the efficacy signal. 1 is that We did over enroll the trial from our original target of 510 to 632.
And we also We note that the separation curve, the Kaplan Meier curve on mortality at least Didn't start to separate until about 18 months in the ATTRACT trial. So the later people drop in, the less impact it should have on the overall result.
Great.
And Eli, can we turn it to you for the KRAS landscape question?
Yes, yes. Thanks for that. I mean, it is early days, as you I mentioned in your question. I think the way you will start is in the refractory resistant population to current Inactive G12C inhibitors. And I think if you see, you know, a roughly 30% response rate in that population, that would be quite exciting.
Of course,
many in
the field believe that the inactive inhibitors, Certainly a great step forward for patients, but they're not seeing the responses that you see with other targeted agents, whether that's TRAC or ALK or these others. And so, you know, We're hopeful. Of course, we have to show this that, you know, in the earlier line setting, it's an inhibitor that A small molecule that can inhibit both the active and inactive form can give those type of responses to patients in earlier lines. So I think you would start in the refractory And shoot for roughly 30%. Of course, it's quite early, and those are so take those as such.
Thanks, Eli. I think we have time for one last question here. Dane, I see Dane from Raymond James is on the line. Dane, if you have a question, we'll
Just maybe 2 easy ones Regarding the upcoming readout of acoramidis, the 12 month time point, We've gotten a lot of questions in, in terms of your team being able to clarify what you think would be a trigger for actually Filing off that 12 month time point in 2022 and whether that filing in your view would could be predicated solely On the outcomes of the 6 minute walk distance test or you would need potentially stat sig outcome at month 12 on cardiovascular hospitalization rate. And then the second one, fairly easy too is, do you think there's going to be a different mix of patient genotypes
Hi. It's John from Fox again. In terms of the 12 month readout, it will be restricted to primary of 6 change in 6 minute walk distance from baseline. The secondary of the quality of life is assessed by the overall score on the PCCQ. We will not be analyzing CVH at the 12 month time point.
That's not Part of the statistical analysis plan has not always agreed with the regulatory authorities. And if we hit our P value, we'll file. That's our plan. And as far as the variant population, We tried to enroll as many as we could. We did pretty well with that.
It's pretty much a typical mix in the U. S. You have Predominantly, the V122I in the Black American population, as well as a a fairly good, sampling of T60A, The so called Appalachian or Scots Irish variant. We do have a lot of participants in the UK where there's also a mix The B122I and 260A predominantly, some B30Ms as well from people who came migrated more from Southern Southwestern Europe. And then as you move through like Spain and Italy, it's a pretty good mix of some of the more rare variants as well as the ones I've mentioned.
Great. Thank you.
Thanks, Dane. I think that's it for questions. Neil, do you want to wrap
it up? No. I just wanted to thank everyone for Spending some time with us this morning and, yeah, appreciate the questions and look forward to, giving you continued updates throughout the course of the end of this year and into next year.