Good morning and welcome to BridgeBio's Second Annual Virtual R&D Day. My name is Grace Rauh. 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&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, Neil 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 cardiorenal 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 Cardiorenal, who is going to be setting the stage for our upcoming top-line phase III data readout for acoramidis, our TTR stabilizer for ATTR. The next cardiorenal session will be presented by Mary Scott Roberts, our Senior Director of Clinical Development at BridgeBio Cardiorenal, who will provide an update on encaleret, our calcium sensing receptor inhibitor for autosomal dominant hypocalcemia type 1, also known as ADH1.
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 three 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. Charles Homcy, Chairman of Pharmaceuticals at BridgeBio, will be introducing BridgeBioX, our new early discovery research program. Finally, to wrap things up, we will hear from our CEO, Neil Kumar, once again for some concluding remarks.
Before I hand it over to Richard Scheller, I just want to remind everyone that today's presentation is expected to run until about 10:30 A.M. Eastern, followed by a 30-minute moderated Q&A that will begin right after the presentations. We do ask that you limit your questions to the topics discussed at today's R&D Day. A replay of the event will be available 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-K 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. 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.
Thank you, Grace, and welcome everybody to the BridgeBio R&D Day. It's now been over two 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 3.4 billion base pairs. We determined from the sequence that there are somewhere between 21,000 and 22,000 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. 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 million changes. That's the chimpanzee, of course.
50 million may sound like a lot on the one hand, however, our genomes are 98.5% 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. 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. Well then, why don't we all look the same? That's because we all differ from each other by about 4 million-5 million variants, with African genomes being interestingly the most diverse. We're 99.8% 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. A major reason then that I don't look like you is because my genome, as I said, is different from you by about 4 million-5 million variants. Now, 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. Of course, that's our major interests at BridgeBio. We are investing in computational genetics and academic partnerships to determine two types, really, of disease variation.
The first type is a monogenetic target, and that's illustrated below with the circles and squares. This is, on the left, a family tree, and the filled-in boxes and circles illustrate individuals that have a disease. 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. 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 million or 5 million positions in the 3.4 billion nucleotides of our DNA. By sequencing different individuals in a family tree, one 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 100% certainty have the disease. Another common form of genetic investigation is 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 one, two, three, four, five, et cetera. 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 than everyone else. There's been tremendous progress in looking at these two types of analysis over the last couple decades. There are hundreds of monogenetic diseases that have been understood in terms of the mutations or the variants that cause the disease. A couple of years ago, I looked, and it was the case that there was more than one monogenetic disease being understood per day, such that there are now over 5,000 of these monogenetic diseases where the disease-causing variant is understood.
Common disease associations, as I described in the GWAS studies, are rapidly increasing, now at an exponential rate, such that there are many, many hundreds of thousands of variants involved in various diseases. I think there are probably over 400 or 500 variants that have been associated with diabetes, for example. 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. 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. We're very excited about the future of being able to help patients, particularly with genetic diseases, to lead better lives. Our next speaker is our CEO at BridgeBio, Neil 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 second-ever R&D Day. Research and innovation is how we serve patients at BridgeBio, 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 Perfectionists," 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 in our ability to connect disease biology to genetic disease and its drivers. Ingredient number one of creating a great company is putting yourself in and around inflection and innovation such as this. 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 million 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 t he innovation in concert with the unmet need are two 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 m any of our colleagues in big pharma don't talk about either.
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. 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 into 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&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 $1.4 trillion in midcap suggests that we need almost $40 billion of new sales every year to live up to this expectation, something we'll never even come close to, despite the bumper crop of approvals we've seen over the last couple of years. What does all of this mean? In the near term, maybe not a lot, but as the winds of hype, narrative-based economics, and irrational exuberance subside over time, we'll find that we're left with only two types of entity.
One, 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 go 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 two 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 what 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 at the level of each disease. Small groups of scientists that are highly incented to just get a 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. Criteria number one 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.
The 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 as, say, acoramidis is, with a peak year sales estimate of $5 billion-$6 billion. In fact, most drugs will sell well less than $500 million 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. Probability of technical success or beautiful science is not all that easy to solve for either.
What's ofttimes the case is that biotechs will work 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 uniformly 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?
For a kidney disease that manifests seven or eight 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 one 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 a s 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 four going to five modalities, and we marry that with ruthless application of cost and time efficiency so that we can get to IND, oftentimes in $10 million 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.
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 two 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. On the other hand, companies with small products but very busy pipelines like BioMarin, Sobi, Ultragenyx, and others. We have the opportunity for the first time to blend these two 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 six years. There are many numbers on this page, and I'll point to just two. First is the two approved products that we've generated over the course of six years. The second, 15 INDs that we've delivered over the course of a little less than six 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 to lead through proof of concept in less than $50 million and in less than three 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 the 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.
Finally, our deliver platform, which is just starting to grow, where we are learning to distribute and commercialize our products with a keen focus on white glove service for the physicians and the patients that we serve, and 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 six years, suggesting the longevity of vision that many of these very experienced R&D practitioners have, with some 250 scientists sitting underneath them, all entirely focused on the efficient prosecution of new medicines within genetic disease. 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. Man, I could literally talk about these programs all day, but I won't. Instead, I want to paint you a picture, 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 one, we got to serve patients with high unmet need. Number two, 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 of itself, our four 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 III data, represent one of the most exciting pipelines in biotechnology today. But there's actually a third wave right behind it, already in the clinic, of some six Mendelian programs, coupled with two oncology programs, where we'll also be delivering proof of concept data in the next 12-18 months. Further offshore, there's a fourth wave, where 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-1 antitrypsin deficiency. You'll hear about a lot of this exciting science later today, but altogether, we believe we've 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. Then, you'll hear about some of the very exciting Wave 4 efforts ongoing. First, the RAS program from Eli Wallace, and finally, from my mentor, Charles Homcy, 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 t hanks everyone for joining this morning. We'll start the review of our R&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 U.S. and globally. 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 HFpEF, heart failure with preserved ejection fraction. 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. In 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.
We'll talk 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 titin, LAMP2, or BAG3. 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.
This has been observed in recent years, as we've seen that historically, in large cardiovascular trials, in the left-hand side here, we see that ACE inhibitors and ARBs, two 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 70 and 100 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 seven and a 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 t his is genetic risk in broader types of cardiology diseases, non-Mendelian diseases. 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. These types of broad genetic risk data help us to identify both new targets to potentially benefit patients with these common diseases, but i n addition, they help us select patients who are more likely to benefit from the therapies that are already available.
Today we'll hear from three programs in the Cardiorenal Division, each of which has the opportunity to work both for a small Mendelian disease 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, Dr. Jonathan Fox, who will talk about the development of acoramidis for ATTR amyloidosis, which is a program where we expect to share phase III top-line data before the end of the year. Second, we'll hear from Dr. Mary Scott Roberts, who is our clinical lead for the development of encaleret for the treatment of ADH1, and she'll share updated phase II data from our ongoing study. Lastly, we'll hear from Dr. Uma Sinha, who will share for the first time clinical data from our GO inhibitor for the treatment of hyperoxaluria.
With that, I'll turn it over to Dr. Jonathan Fox to get started on acoramidis.
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, acoramidis for transthyretin amyloidosis. Transthyretin amyloidosis has a prevalence of about 400,000 patients worldwide. The pathophysiology is that of a systemic disease that involves many organs and tissues, but most commonly presents as either a 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 i t 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 T119M 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. Again, as I mentioned, the most devastating consequences of this disease process are the cardiomyopathy or ATTR wild type or variant CM, which is involved with the deposition of wild type or variant, f or 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 three to five 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 V30M variant found endemically in areas of Portugal, Sweden, and Japan. The onset is between the ages of 30 and 50, which is also progressive and fatal with a median survival of 5-1 0 years from diagnosis. We're now seeing a rapid increase in patient finding and case finding driven by a non-invasive diagnostic technique that was developed over the last decade.
On the left-hand side of the slide, you see a timeline of the rate of diagnosis in terms of the number of patients diagnosed with the disease or incidence, and starting at around 2008 with first the advent of cardiovascular magnetic resonance, 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 non-invasive 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 can be attacked in the way that we propose to do so, let's take a look at the normal metabolism of healthy TTR in healthy adults. The protein is produced by the liver.
It is secreted into the bloodstream as a four-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 is otherwise cleared by normal mechanisms of clearance of plasma proteins. However, in susceptible individuals, those who carry disease-causing variants or who are subject to some ill-defined processes associated with aging, that normal cycle produces a sidebar 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 two 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 aging dissociates into monomers, which then aggregate and can be deposited in tissues in a pathologic way. We know that people who carry the T119M variant are protected from the disease, and this was shown originally in Portugal, where members of families carrying the V30M disease-causing variant seemed to be protected from the disease, and they were found to carry one copy of the disease-causing variant and one copy of the disease protective variant, which protected them from becoming ill.
If we can mimic this mechanism by adding a stabilizer molecule like acoramidis, 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. For example, the L55P 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 V122I 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 third row.
Finally, the T119M 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 III ATTR-ACT study of tafamidis in ATTR cardiomyopathy tested two doses of that drug, 20 mg and 80 mg of the meglumine salt versus placebo. Patients receiving 80 mg of tafamidis versus the 20 mg 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 mg versus 20 mg in terms of clinical benefit was evident on all-cause mortality in an analysis of the ATTR-ACT 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 acoramidis. In this graph, you see two 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 mg dose.
The 26 micromolar represents the reported peak plasma concentration at that same dose, compared with acoramidis 10 micromolar, which is a little bit higher than the trough steady-state concentration of acoramidis that is used in the clinic. This shows that acoramidis demonstrated near complete TTR stabilization in vitro at these clinically relevant concentrations. Getting onto the clinical data, we performed a phase II 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 II studies in which in the original randomized placebo-controlled study, 49 patients underwent randomization, 17 to placebo, 16 to acoramidis hydrochloride 400 mg, and 16 to acoramidis hydrochloride 800 mg. Those results have been published in the Journal of the American College of Cardiology.
Following the randomized portion of the study, we invited those participants to come into the open label extension. Two people declined for logistical reasons, and t he rest came into the open label extension. What we presented as of 2019, we knew that six people had discontinued study. Three had died, one had received a heart transplant, and t wo had discontinued for other reasons. As of the end of August of 2019, 41 patients continued to participate in the open label extension. The outcomes from this phase II study primarily were safety and tolerability, so w e recorded adverse events, clinical events, and 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 II trial.
In the placebo arm, 15 people or 88%, reported any adverse event, and in the acoramidis pooled dose group, there were 21 adverse events. These were largely mild or moderate in severity. There were several serious adverse events, two of them in the placebo group and one of them in the acoramidis 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 a 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, w hereas in the active dose group, all participants had an increase in their serum TTR, which showed a dose effect. 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. They, of course, as a result of the stabilization across the board, they experience, proportionally speaking, a larger increase in serum TTR.
We looked at the biomarkers N-terminal pro-BNP and troponin I in this study. This shows the follow-up in the long-term extension, essentially showing that both N-terminal pro-BNP and troponin I remained stable in acoramidis-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 III program consists of a single study, the ATTRibute-CM cardiomyopathy trial. This embedded phase III 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, New York Heart Class I through III, 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 six-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.
Six-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 six-minute walk distance occurs in multiple cardiopulmonary diseases. Dr. Matt Maurer of Columbia University has been quoted to say that the six-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 six-minute walk distance data in ATTR cardiomyopathy and healthy cohorts as demonstrated in the ATTR-ACT study.
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-m annual decline in six-minute walk distance performance. The black line in the middle shows the tafamidis-treated group in the ATTR-ACT study that was compared to the placebo group in the blue line, showing a much steeper decline. The hypothesis behind our 12-month readout is that near complete stabilization of TTR by acoramidis may slow or halt functional decline in the six-minute walk distance compared to baseline.
We have several important upcoming milestones. At the end of 2021, we'll have the acoramidis Part A top-line data from ATTRibute-CM. Mid-2022, we anticipate filing for registration both in the U.S. by filing an NDA and in the European Medicines Agency, filing a marketing authorization application. In 2023, as the participants continue through Part B, we'll have the readout of the acoramidis 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 Dr. Mary Scott Roberts, our medical lead for the encaleret program, developing that drug for autosomal dominant hypocalcemia. Dr. Roberts.
Thank you, Jonathan. Autosomal dominant hypocalcemia type 1, or ADH1, is a condition that impacts approximately 12,000 people in the U.S., such as Alexis and her son Jackson, pictured here. While outwardly Alexis and Jackson appear to be quite healthy, we know that ADH1 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 ADH1, 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 ADH1, would lead to resolution of the symptoms and the underlying laboratory abnormalities that these patients have, and would be convenient for the patients. Encaleret 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 ADH1 disease mechanism in more detail. As its name would suggest, the calcium sensing receptor senses and regulates blood calcium in order to maintain normal calcium homeostasis. In ADH1, activating variants in 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 ADH1, 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.
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 that these patients experience, including nephrocalcinosis, which is calcification of the actual kidney tissue itself, nephrolithiasis or kidney stones, and both of these can lead to renal impairment, resulting in chronic kidney disease. A recent systematic review of the medical literature found that the median age of ADH1 diagnosis is 25 years, with a range from infancy up to 77 years. 42% of these patients present with severe symptoms like seizures, while 31% present with mild to moderate symptoms.
We know that the degree of ADH1 symptom severity is directly associated with the blood calcium levels, as you can see in the graph on the left. In dark blue, the patients who presented with severe symptoms had significantly lower blood calcium levels than those patients who presented with either no symptoms or with moderate symptoms. The currently available medical intervention for patients with ADH1 includes oral calcium supplements and active vitamin D, which is a prescription medication. 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.
One thing that's really important to note here is that it's incredibly hard to increase the blood calcium without further increasing the urine calcium in these patients. If you think about it, you're basically adding calcium to a system without addressing the underlying defect, and that results in spilling of the calcium in the urine. 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 in their ADH1-related symptoms. These data suggest that there remains a large unmet need for better treatment options for this patient population. Here, we can see the two 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 circulation. In ADH1, the overactive calcium sensing receptor tells the parathyroid gland to go to sleep and not to release PTH into the circulation, despite the fact that the blood calcium levels are quite low. On the right-hand side, the calcium sensing receptor 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.
These are the exact locations that encaleret is expected to act to dial back the activity of those overactive receptors in patients with ADH1. What we expect to see with encaleret treatment is represented on this slide by the light blue arrows. By targeting both the parathyroid glands and the kidneys, encaleret is expected to increase PTH secretion, resulting in normalization of the corrected blood calcium while simultaneously maintaining a normal urine calcium. That's exactly what we're trying to demonstrate in our phase II study seen here, which consists of four sections. Period 1 is a dose exploration phase in which six subjects receive the same escalating doses of encaleret. Period 2 is a dose optimization phase in which the six subjects in Period 1 plus an additional seven subjects, for a total of 13, underwent individualized encaleret dose titration.
One thing to note is that prior to Periods 1 and 2, all of the subjects discontinued their active vitamin D one to two days prior to the first dose of encaleret 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 t hey can continue on encaleret 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 III study.
The key study objectives in the phase II study include safety and tolerability of encaleret, as well as the effects of encaleret 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 encaleret treatment during Periods 1 and 2 were quite different. As you can see on the left-hand graph, in Period 1, all six subjects received the same fixed escalating doses of encaleret, with the exception of one 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 180 mg twice daily, in line with where we finished dosing in Period 1.
But then we realized that the optimal encaleret dose is actually lower for most of the patients, and so w e decreased the starting dose to 90 mg twice daily. Over the five days of Period 2 , you can see that the mean encaleret dose decreased, and by day five, the dosing range was quite wide, with some patients requiring 180 mg twice daily, while others required 10 mg twice daily. These are the baseline characteristics of the study population. 13 participants with a mean age of 39 years and nine 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.
Three-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, encaleret has generally been well-tolerated through Periods 1 and 2 , 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 encaleret treatment included hypocalcemia, hypophosphatemia, and hypercalcemia, all of which were transient and resolved spontaneously or with encaleret dose adjustment. Here, we can see the individual and mean responses on days one and five in the six subjects who completed Period 1 . The day one PTH and corrected calcium levels, which are represented by the gray bars, were collected just prior to the first encaleret 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 five of encaleret treatment, represented by the blue bars, all six 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 participants had decreases in their 24-hour urine calcium, three of which had undetectable levels on days four or five . These figures show the mean pharmacodynamic responses on days one through five in the 13 participants that were treated with individualized twice-daily dosing in Period 2.
In the upper panel, you can see that the albumin-corrected blood calcium increased gradually with the mean reaching the lower limit of the normal range by the end of day two and maintaining within the normal range through day five. Concurrently, the 24-hour urine calcium in the bottom panel decreased into the normal range within the first 24 hours of encaleret treatment and remained within the normal range through day five.
One thing that I'd like to note is that there is a mild increase in the mean 24-hour urine calcium on day five, and t his is likely reflective of the need for ongoing encaleret dose adjustments, as well as the increases in blood calcium. Similar to what we saw in Period 1, the PTH responses to encaleret were quite robust, increasing from a very low level at baseline to well within the normal range within just 30 minutes following the first encaleret 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 five of encaleret treatment. To summarize, in the 13 patients with encaleret who enrolled in the phase II study, encaleret treatment led to a normalization in the mean blood calcium, while at the same time normalizing the mean 24-hour urine calcium excretion. All participants had increases in PTH and decreases in phosphate into the normal range. Encaleret was well-tolerated with no serious adverse events reported, and i mportantly, these consistent improvements in mineral homeostasis suggest that encaleret may be an effective treatment for patients with ADH1.
Our team is incredibly excited about the next steps in 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 II study after all of the participants complete the 24 weeks in Period 3, as well as the initiation of our phase III registrational study. Thank you for your attention, and I look forward to any questions in the Q&A portion.
Thank you so much, Mary Scott. Next up, we have Eric David, the CEO of BridgeBio Gene Therapy. Eric.
BridgeBio Gene Therapy has made tremendous progress since I spoke to you at R&D Day a year ago. We have two 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&D. I'm thrilled to be able to talk to you today about BBP-818, our AAV program in galactosemia, a disease that many of you already know has significant unmet need. 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 TSC1/ 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 TSC 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 Maguire at Mass General, and with Aravind Asokan at Duke. If you look at the entire BridgeBio Gene Therapy portfolio together, 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 w hile Bridge remains agnostic to modality, sometimes you're just going to 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 sq ft of dedicated CMC and R&D space in Raleigh, where we can do all of our research-grade manufacturing, our GLP tox manufacturing, w e 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 a great deal of money and time on CMC. And we still maintain our dedicated GMP space agreement with Catalent. 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 Dr. 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 Dr. Kent Lai from the University of Utah School of Medicine, currently in IND-enabling studies. 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.
There has been shockingly little innovation in this disease since the development of exogenous steroids in the 1950s. These patients still have a three- to four-fold higher mortality ratio than their age-matched 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. 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. Therefore, it's the only approach that has the potential to get them completely off of steroids or significantly reduce their daily steroid dose.
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%- 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 were able to induce in the patient's adrenal glands. We found that in the E to the 12 range, we were able to get as high as 9%, so well into that 5%- 10% range. Then, dosing in the mid E to the 13 range, we were able to get as high as almost 25% of wild type enzyme.
Our phase I/II first-in-human trial is currently open and enrolling patients 18 years and older. We plan to dose across three dose groups, three patients in each group, and we'll escalate based on safety. We can also expand at any dose needed. 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 updates on this program in 2022. For our AAV9 therapy for Canavan disease, we have the privilege of working with Dr. Guangping Gao at UMass.
Now, all of you know Dr. 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. This is an absolutely devastating neurological disease, where patients present typically in the first six to eight 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 first two 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 i t's just all around a completely devastating disease.
We designed BBP-812 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 first-in-human phase I/II trial. We're dosing at two dose levels, and we can escalate or expand based on safety. 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 can also measure it 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 Canavan disease in parallel with this.
I wanted to give a quick update on our AAV therapy for TMC1 hearing loss, which, as you recall, is a collaboration with Dr. 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. We deliver this one directly into the cochlea, so it only requires very small amounts of vector. This is the only intervention for TMC designed to restore natural hearing across a wide range of frequencies. 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. Dr. 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. 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. We're hugely excited by the data we're seeing there.
This program continues through R&D enabling studies now. Type 1 galactosemia, or classic galactosemia, is caused by a deficiency in galactose-1-phosphate uridylyltransferase , or GALT. This impacts an estimated 7,000 patients in the U.S. and EU. Now, dietary restriction alleviates the acute life-threatening toxicity in infants, but e ven 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 Dr. Kent Lai at the University of Utah, we developed 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 p atients with classic galactosemia who have less than 1% of normal enzyme activities have the most severe disease.
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, b ut patients with just a little over 1% of the GALT 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, patients get buildups of Gal-1P, galactose, and galactitol, which are all toxic in their own way, and t hey have a deficit of UDP-galactose, which is essential for normal myelination. Genotype-phenotype correlation studies have shown that patients with more than 10% of normal GALT activity are asymptomatic, and patients with between 1% and 10% have much lower disease-related complications.
We've been working with Dr. 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. What you see on the right-hand of the slide is brain levels of GALT activity. 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. 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. I'll leave you with this final slide that I hope summarizes the key themes from today, t he right team, the right manufacturing model, and a robust pipeline of high unmet need and beautiful science. Thank you for your time.
Thank you so much, Eric, and n ow, I'd like to introduce Uma Sinha, our Chief Scientific Officer. Uma?
Thank you, Grace. I'll be talking about the third wave of programs. At BridgeBio, we continue to target monogenic diseases that we can treat at their source. This is pretty much the hallmark of our drug development activities, and I will discuss three individual programs which are already in the clinic. Some of the work has been done in healthy volunteers, some of it in patients, so t hese are fairly representative examples of what we are doing at BridgeBio. The first program will be on primary hyperoxaluria and frequent stone formers, t his 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. The third program in our RDEB is from our dermatology portfolio. Let's jump right in into the cardiorenal program. This is in primary hyperoxaluria type 1 as our proof-of-concept indication.
This is a fairly rare disease with a prevalence of about 5,000 patients in U.S. and U.K. Just to define what exactly is hyperoxaluria, it's a condition where there's excessive 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. I 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.
In this particular approach that we are taking to primary hyperoxaluria, 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 targeting is treating PH1 at its genetic source. In healthy individuals, the enzyme AGXT is fully functional, and oxalate does not build up. However, in patients who have inherited mutations in AGXT, the glyoxylate builds up, t his being the substrate of oxalate results in formation of kidney stones. 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 PH1 at its genetic source. Essentially, what happens is when GO is inhibited, both in animal models and in humans, the glyoxylate doesn't build up.
Th e reaction stops at the glycolate stage, and glycolate is safely excreted. Our approach is targeting the pathophysiology, and we want to reduce oxalate, not just in PH1, but also in broader clinical indications. What is the stage of this program? Right now, we are in phase I, 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. We 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. 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 GO. I want to emphasize that we are right now taking glycolate level to a level that has not been reported in the literature or by any other agent. We anticipate getting PH1 data in 2022, as well as the phase II/III initiation. What did we learn from this particular proof of concept of targeting GO to the fullest extent possible?
We have the potential for expanding this learning to recurrent stone formers. That's obviously not a rare disease, t he prevalence is 1.5 million in Europe and in the U.S. What is already known from the literature, as well as from our discussion with key opinion leaders, is excess oxalate excreting into the urine is a major risk factor for calcium oxalate stone former and idiopathic stone formers. This is likely an opportunity. We have learned a lot from inhibition of GO in healthy volunteers, w e learn more in PH1 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, they had a predisposition to disease pathology.
Then, the field expanded with the use of TTR stabilizer. In wild-type patients, we saw therapeutic benefit. 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. Very similarly, we are anticipating taking our lessons from PH1 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, p revalence is about 7,000 patients in U.S. and U.K. 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. 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. Where exactly is this program now? I want to remind you that the agent that we are studying is ribitol, which is a naturally occurring compound, and it's being investigated both in healthy volunteers and in patients. What is the disease pathology here? The disease is caused by partial loss of function of the fukutin-related protein . What this does is the patient can no longer sufficiently glycosylate the target protein α-DG in muscle cells. Fully glycosylated α-DG, essentially, is like a shock absorber.
When α-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 supraphysiologic levels of the substrate. We are providing ribitol, which in turn will get converted to CDP-ribitol, and we see this as a potential to rev up residual FKRP enzyme activity and take the target protein α-DG to its fully glycosylated form. I want to talk a little bit about the phase I and phase II data. The phase I 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.
This property, a very desirable one, has shown that we can predict exposure all the way up to a total daily dose of 18 g, which is a rather large amount by any measure. The healthy volunteer data was very helpful in informing the initial doses of the phase II study, which we have started in LGMD2I patients. The data will be reading out in 2022. We are also anticipating presenting data at Muscular Dystrophy Conference early in 2022. What will we be pursuing in the patients? We are 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 w e will be measuring that. We will be measuring the all-important PD marker, which is α-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 II patients. This data, in turn, will be informing our phase III dose selection. In summary of the phase II 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 third representative program that we chose to discuss today. Recessive dystrophic epidermolysis bullosa is a fairly rare disease, t he prevalence is about 2,000 patients in U.S. 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 RDEB, as well as 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 in RDEB is caused by mutations in collagen VII. In healthy humans, collagen VII works essentially as an 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 VII, so essentially, they cannot hold the epidermis and the 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 I and shown a well-tolerated profile. The dose-dependent increase in C7 has been particularly gratifying, and t hat's because C7 is a rather large protein. It was good to see that it's actually reaching its target. We have these elevations in collagen VII deposition. We have followed them by immunofluorescent staining in biopsy samples. The C7 is actually reaching the dermal epidermal junction, so t he intended target site of action is being occupied. Phase II is currently ongoing, and w e 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 my presentation, I've highlighted three 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 five mid and late-stage programs which are bringing up the rear. We have ATTR, achondroplasia, ADH1, RDEB, and LGMD2I.
There are three earliest clinical programs which are currently in early studies in healthy volunteers or in patients, and there are also additional preclinical programs which are bringing up the rear. I want to highlight that I talked about three of our Wave 3 programs, but there's a lot of other things happening this year. The acoramidis program in ATTR will be reporting its Part A phase III readout by the end of this year. Soon after, in 2022, we will have data in achondroplasia, RDEB, LGMD2I, as well as PH1. Thank you.
Thank you so much, Uma. 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 potential first-in-class research programs. Our FGFR inhibitor, TRUSELTIQ, 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 TRUSELTIQ in underserved patients, including phase III studies in first-line cholangiocarcinoma and in gastric cancer. Today, I'll focus my presentation on two of our RAS research programs and BBP-398, 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 its oncogenic function cannot be understated. We have multiple approaches to target RAS-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 dynamic 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 two other RAS programs, for which I will provide an update today, are both positioned to be potentially first-in-class. One is a G12C inhibitor project where our inhibitors bind directly to both the active GTP-bound and inactive GDP-bound states of KRAS G12C. The other is a new approach that blocks RAS binding to the signaling effector PI3Kα. As RAS PI3Kα interaction plays an important role in oncogenesis, but little to no role in normal cell function, we anticipate that this approach will provide anti-tumor 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 dynamic 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. Our approach of targeting the active and inactive forms of KRAS G12C directly, we believe will provide a superior therapy to patients suffering from KRAS G12C cancer compared to inhibitors that block only the inactive form. First, our inhibitors block the active effector binding form of KRAS G12C, which should result in more pronounced and faster inhibition of oncogenic signaling.
Second, by strongly and rapidly inactivating both the active GDP-bound and inactive GDP-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 active/inactive state inhibitors. As shown in the table, our KRAS G12C inhibitors rapidly and completely modify KRAS G12C in both the active GTP-bound and inactive GDP-bound states. In contrast, neither Amgen 510 nor Mirati 849 can modify the active GDP-bound state of KRAS G12C at all. Our rapid and complete modification of the active GTP-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 H358 lung cancer cell line than the KRAS G12C inactive state inhibitors. Our KRAS G12C dual inhibitors can block oncogenic signaling in the cellular context, a s shown in this KRAS G12C A59G 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 inhibitor's 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 than G12C off inhibitors. We believe this is a direct result of our inhibitor's ability to quickly engage and 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 six, BridgeBio's dual KRAS G12C inhibitors are approximately five times more potent than the competitors. By day 34, our inhibitors are greater than 30 and 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 PaCa-2 KRAS G12C mutant cell line, and a single dose leads to sustained inhibition of phospho-ERK through 48 hours, the last time point taken. Our lead inhibitors have now moved into efficacy studies where we are seeing rapid regression of established tumors.
In this study, once daily oral treatment with one of our inhibitors at 30 mg/kg results in rapid regression of established MIA PaCa-2 tumors and is well-tolerated. The second research program I will highlight today is our PI3Kα-RAS protein-protein interaction inhibitor, what we refer to as our PI3Kα breakers. This program also fits with our strategy of targeting drivers in oncology. PI3Kα is the second most frequently mutated oncogene behind only RAS, making effective targeting of PI3Kα of the utmost importance. As is well documented, there are two primary means of activating PI3Kα. In normal and tumor cells, PI3Kα can be activated through growth factor receptor tyrosine kinase mediated direct activation. Additionally, and specifically in tumor cells, PI3Kα can also be activated through direct binding interaction with RAS. Our approach inhibits RAS mediated activation of PI3Kα, specifically in tumor cells.
In contrast, as illustrated here with alpelisib, PI3Kα kinase inhibitors block AKT signaling in both normal and tumor cells. The targeting of PI3Kα indiscriminately, however, results in significant issues, as in normal tissues, the PI3Kα/AKT pathway is critical for glucose insulin homeostasis. As a result, PI3Kα kinase inhibitor treatment leads to metabolic dysregulation. For example, greater than 60% of patients in alpelisib's pivotal phase III trial experienced hyperglycemia, with a third of patients experiencing grade 3 hyperglycemia. This resulted in significant dose discontinuations and disruptions and exclusions of patients with metabolic syndrome. 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, PI3Kα, and RTK- driven cancers a novel therapeutic option both as monotherapy and in combination. Validation of our PI3Kα RAS breaker approach comes from genetic studies in mice with two- point mutations in the RAS binding domain. These mutations block RAS's ability to bind and activate PI3Kα. 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 PI3Kα breakers, as shown in the table, compared to PI3K kinase inhibitor alpelisib. Importantly, our inhibitors bind selectively to PI3Kα, do not bind to RAS, do not affect PI3Kα kinase activity, and are agnostic to the RAS isoform involved in activation of PI3Kα.
Our novel approach to PI3Kα breakers is clearly differentiated from kinase inhibitors. Here, we evaluate the response to insulin-like growth factor 1 in a cell line where PI3Kα has been demonstrated to be activated by insulin receptor substrate compared to a cell line where PI3Kα activation is dependent on RAS. As shown, both pan PI3K kinase inhibitor and alpelisib inhibit phospho-AKT in both cell lines, whereas our PI3Kα breaker only inhibits phosphorylation of AKT in the RAS-dependent cell line. These data suggest that our PI3Kα breakers may avoid the on-target hyperglycemia associated with PI3Kα kinase inhibitors. Let's now move to BBP-398, 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-EORTC Molecular Targets and 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 signaling transduction pathway. SHP2'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. BBP-398 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. Its predicted high oral bioavailability and 10–15-hour human half-life should support once daily dosing. Based on strong preclinical data, we have prioritized three combinations with G12C inhibitor, EGFR inhibitor, and anti-PD-1 antibody nivolumab.
These last two combination studies will be conducted in collaboration with our partners LianBio and BMS, respectively. Preclinical mouse efficacy studies with BBP-398 have shown significant anti-tumor activity in multiple models with maximum efficacy achieved with 100 mg/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 16-20 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 in combination studies. BBP-398 is currently in a dose escalation phase I in advanced cancer patients with MAPK- pathway alterations.
To date, BBP-398 has behaved as expected with observed pharmacokinetics and pharmacodynamics in line with predictions. We will explore four monotherapy dose expansions at the recommended phase II dose and initiate combination studies next year. In summary, we have demonstrated our ability to develop precision oncology agents with the approval of TRUSELTIQ, and we have a promising pipeline of programs following close behind, including our novel KRAS G12C dual GTP/GDP inhibitor and our PI3Kα RAS breaker efforts, as well as our differentiated SHP2 inhibitor, BBP-398. As we look forward to a productive 2022, we anticipate identification of a RAS development candidate, presentation of BBP-398 phase I clinical data, and initiation of BBP-398 combination studies. Thank you.
Thank you so much, Eli. Now, I'd like to welcome Charles Homcy, Chairman of Pharmaceuticals at BridgeBio.
Good morning, everyone. It's my job as part of R&D Day to tell you a little bit about BridgeBioX. As most of you know, BridgeBio was founded around the concept of Mendelian diseases, where a single gene contributes the entire phenotype. Think about sickle cell disease, think about familial hypercholesterolemia. In that case, a single gene causes all of the complications of sickle cell disease, essentially, or all the complications of high cholesterol, coronary artery disease, et cetera. What is going to be new for BridgeBio is this effort, BridgeBioX, where we're going to look at more complicated genetic space. By that, I mean diseases where multiple genes contribute not 80% of the phenotype, but 5%, 10%, and maybe even less, so w e're going to go earlier. What makes this complicated is to understand the genetic leverage points.
What are those diseases where a single locus, if we target them with a drug, will have an important impact on a so-called polygenic disease? 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. Now, we're actually going to be using our statistical and computational genetics group within BridgeBio, who's quite excellent by the way, to interrogate large databases and find genes that likely contribute in a causal manner to polygenic diseases. 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 going to 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 throughput screening, cryo-EM. You name it, we need to have it. Most importantly, and for the most part, a really wonderful chemistry group, which we already have, but we're going to have to add to that. 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 physician's look at disease on the inside, and t hat is all happening within BridgeBioX and its reach into the BridgeBio organization. That's kind of a small look at BridgeBioX. I guess the labs are going to be down on the Stanford campus. 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. A really remarkable effort. At the end of the day, helping patients is just about the best thing in the world, so t hank you very much, r eally appreciate it. We all do.
Thank you so much, Charles. Now to wrap things up, I want to bring Neil Kumar, our Founder and CEO, back up for some concluding remarks.
Well, thank you again, everyone, for your time and interest. Across a great number of these programs, 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 for genetic disease. We'll move into Q&A now.
Thank you, Neil. Before we kick off Q&A, I just want to quickly run through directions for the Q&A process. You can dial in to ask a question using the numbers presented on the slide. To ask a question, please press star nine. To unmute, please press star six. When asking a question, we ask that you please mute or close the webcast video. I will now turn it over to Cameron Turtle, who is going to be moderating our Q&A. Thank you all.
Great. Thanks, Grace. We'll start the Q&A with Salim Syed from Mizuho. Salim, if you can unmute yourself and please go ahead.
Great. Can you hear me?
Yep.
Yeah. Okay, great. Thanks so much for all the color today, guys, s uper 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.
We welcome you.
I had a couple questions maybe on acoramidis, if I can, and then maybe one on the other programs. Neil, I noticed you mentioned in there peak year sales for acoramidis of $5 billion or $6 billion, which is higher than the $4 billion that was in the Eidos merger docs. I'm just curious what has changed, if anything, for that higher number. Do you prefer I just ask all my questions now or just sort of get back?
No, let's go through them. That's fine.
Okay. Second question on acoramidis is, as we're approaching this phase III readout here, obviously , the market's not interpreting this trial as risk-free. I presume part of this is because when we look at the six-minute walk data here from Pfizer, it was never baseline adjusted for the 80 mg versus 20 mg tafamidis. I think, everybody understands that acoramidis stabilizes much more of the tetramer. How do you guys get people comfortable here with the curve if we're looking at TTR stabilization on the X-axis and six-minute walk, not mortality on the Y-axis, as we stabilize more of the tetramer, that you will, you know, 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?
This may be on the last question. I'll just ask and then tolerate question. Just given the high degree of variation in dosing there with 10 mg daily and I think it was 360 mg daily, just curious how you guys are thinking about the strength that you would need here and the pricing framework, just given the multiple strengths and the titration schedule. Thank you.
Yeah, sure. Maybe I'll take the first one, and I'll kick it over to Jonathan for the second question, and Mary Scott for the [crosstalk].
The 360-mg daily, j ust curious how you guys are thinking about the strength that you would need here.
Sorry. Okay. I'll share some background notes. Just in terms of the peak year sales, Salim, I think what we've been encouraged by is the continued growth of the prescribing base for tafamidis, both within the U.S. and actually ex-U.S., which has outperformed our expectations. We're up to some 27,000 claims for ATTR-CM, and that number continues to grow exponentially. If you look at the prescriber base, which is a little bit above 1,000, what you can see is a great number of cardiologists that are really sort of not AMC-associated cardiologists are picking up this disease.
With that, we're able to refine our numbers up in terms of penetrance closer to that couple hundred thousand range, ultimately, which we think is consistent with that 13%-15% of HFpEF patients having ATTR-CM, which in turn, I think with some fairly conservative modeling, gets us closer to that $5 billion-$6 billion number that we spoke about. I think, we continue to project a best-in-class profile within this disease state, so a ll that is what adds up to the updated numbers.
In terms of the six-minute walk response function, if you will, with stabilization on the X-axis and six-minute walk on the Y-axis, maybe I'll kick it over to Jonathan for some comments there.
Yeah. It is Jonathan Fox here. A 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 a gentle decline in six-minute walk performance in an otherwise healthy age-matched cohort of about 7 m per year, in people who are in their seventh, eighth decade, so to speak. 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 that then misfold and aggregate and get deposited.
I mean, the phase II 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 r eassuring 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. It's really hard to tease apart what the 20 mg versus 80 mg in ATTR-ACT really might have done. 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 design this somewhat innovative approach to having an embedded Part A readout at 12 months.
Mary Scott, you want to handle the encaleret question?
Sure. The encaleret dose titration will be fully outpatient in the phase III study, with laboratory assessments that'll be performed on a semi-regular basis with decreased frequency over time in order to maintain a blood calcium in the normal range. This is similar to other endocrine disorders, f or 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. The exact dosing schedule will, of course, be determined after our conversation with the FDA at the end of phase II meeting. That's where we're thinking at this point.
Salim, it's probably a bit early for pricing on this one. The wide range of dosing does create some challenges there. As we get into the outpatient setting and see where most of the patients end up, then we'll probably have a better answer for that as we get into the phase III.
Okay. Thanks, Salim. Let's move on. Anupam, you want to get going next?
Hey, guys. Thanks so much for taking the questions this R&D Day. Two quick ones from me. Thinking about ATTRibute-CM, 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 II OLE results, o r are you guys going to stay blinded to those results till 2023? If we're going to get some type of look, how are you guys thinking about it in terms of curve separation? Second question, know the focus in 4Q is on six-minute walk distance, s hould we be thinking about similar baselines, relative to what we saw in ATTR-ACT for tafamidis, which I think is around 350 m? If tafamidis showed a 25-m decline at 12 months, what would be a win scenario for you?
Thanks so much.
Hi, Jonathan here. To the first question, I would say that we will 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 as an endpoint and CVH as an endpoint, we will remain blinded to those until the end of Part B. 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-matched cohort, t hat, to me, would be a pretty outstanding result. Even if we split the difference between that optimal result and what you saw in ATTR-ACT at 12 months, I still think that would be a major improvement in clinical benefit.
Great. Thanks, Anupam.
Thanks for taking our question.
Yeah. Should we go to Ellie next from UBS?
Hey, guys. Thanks so much for taking the questions, and thanks for all the color on the programs. Just for TTR again, 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 trial, just like given the changes in diagnosis and I guess different understanding of the disease now versus when Pfizer had started their phase III. Also, just on TTR, I guess what could be the potential impacts of COVID, I guess, on the placebo arm, or also even the study broadly? Then, I'll follow up after with some questions on gene therapy.
Hi, it's Jonathan again. To the first question, I apologize I missed that one on the last go-round. In terms of baseline characteristics, very similar to what you saw in ATTR-ACT. In terms of baseline biomarkers, baseline six-minute walk, a really very similar patient population. 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 ATTR-ACT. Hopefully, that happens across the board in drug development, that you learn from the experiences of others if they've come before you. In terms of I'm sorry, the next one was?
COVID impact.
Sorry?
The impact of COVID on [crosstalk].
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 U.K. and Spain, and Italy, where, as you know, it wasn't just the United States and other countries having a big problem with it. Thankfully, for whatever reason, we were able to do a lot of telephone visits for routine safety checks and get people in for their six-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. Right now, the data collection seems to be going pretty well. Is there another one?
No, I think that's it. Geoff, can we go to you from Bank of America?
Guys, can you hear me?
Yes.
Yes.
All right. Perfect. Just a couple. Another one on acoramidis. When you look at the data, I'm just trying to reconcile maybe other points of differentiation when you look at TTR stabilization, h ow 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? 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?
All right.
Yeah.
Do you want to take over?
Yeah, I can take over. Thanks, Geoff, for the questions. I think in terms of stabilization and outcomes, a couple of things have been well-trodden within the space that you know. Number one, obviously, from the genotype/phenotype, every time you 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, diflunisal outperforms tafamidis at 20 mg, so you can see ever-increasing stabilization leading to better clinical outcomes. I think most importantly, in the cardiomyopathy space, you saw 80 mg outperform 20 mg, almost a 20% relative risk reduction in terms of mortality. There's a broad set of data that suggests every time you do better in terms of stabilization, y ou should do better for these patients.
As Jonathan suggested in his earlier comments, you can kind of weave this, connect the dots from mortality back to six-minute walk data based not only on some of the ATTR-ACT data, but also from the Lane paper where one can connect hazard ratios to six-minute walk performance in this patient population. I think all of that case has been made. The degree to which the response function is linear versus something else, I think is something we'll have to see and we're testing, obviously, in this clinical trial. That's question number one. I guess, question number two on gene therapy strategy, a couple of things inform our gene therapy approach. Obviously, we've been willing to cut across a wide variety of organs, 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 two programs today where you're looking to replace somewhere between 10%-30% of the wild-type enzyme, which is a low bar, versus some of what you see in certainly neurodegenerative diseases where you need to get close to 100%, but you can't go over and you can't go too terribly under. 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 million. I think in gene therapy, especially given the FDA's recent guidance, you're going to be looking at $30 million-$40 million INDs. So, one needs to be very careful in the selection of the end market so that the expense can be justified on a risk-adjusted basis. That's at least two of the criteria that we use.
Look, we're bullish 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. Co ngrats 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. 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 third-party drugs, like COMT inhibitors, like tolcapone, and whether like you can actually accurately replicate physiological conditions, and how this translates to predictability of clinical outcomes? Our second question, probably for Mary on encaleret is, will you have six-month data before year-end, and before your planned FDA meeting? Do you still think about a 50% reduction in serum calcium as the appropriate endpoint here?
Just, what your updated thoughts are post your phase II data. 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? 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? 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. They've given very consistent results, both when spiking drug in vitro and in taking samples from both non-human mammals and humans once we got into the clinic. Even in healthy volunteers, very consistent results that acoramidis across the entire dosing interval after the dose we took forward into phase III does result in near complete stabilization. How that relates back to clinical benefit, that's the experiment we're running now. We do have tantalizingly reassuring data from the phase II program, but a s I mentioned earlier, it's small numbers. The OLE obviously uncontrolled, but i f 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. With respect to the ability of other plasma proteins like albumin to interfere with the interaction of the drug with the target, we know that the protein binding for acoramidis is rather modest compared to most small molecule drugs, including tafamidis, which has very high protein binding, so that the free fraction that's available to interact with the target is limited. 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 imagine, there's probably no drug that I know of that works 100% all the time in 100% of people who get it. Maybe , there are a few people out there that might benefit from tolcapone, but I don't hold it up as 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 when you look at serum TTR levels, as Neil mentioned, the more destabilizing the mutation, the worse the clinical outcome for people who carry those mutations, higher the penetrance, earlier age of onset, more rapid progression. 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 acoramidis, everybody's TTR level goes up into the normal range, i t doesn't overshoot.
It seems to restore what the normal balance might be and all the normal physiological functions of TTR. 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 encaleret data for the end of the year.
Sure. Thanks. For your question on encaleret, we plan to discuss the data that's available from our live phase II database with the FDA at the end of phase II meeting. Then, we'll plan to present the results from the full phase II study that includes that six-month outpatient period early next year, b ut we do know that the preliminary data shows continuation of the response that you saw today during the presentation. As far as the endpoints go, we think that the same endpoints that we presented for the phase II study, blood and urine calcium, 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 disease.
Thanks, Mary Scott. Eli, we'll turn it over to you to answer your question.
Yeah. Thank you. Yeah, 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 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 form, 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, t hat, as far as I know, from published data, that hasn't been shown with other inhibitors. I will tell you, our early xenograft studies, we are outperforming the inactive inhibitors on an EC level with once daily dosing quite significantly. 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 candidate.
Awesome. Thanks, Eli. We'll go to Raghuram next, if we could, from H.C. Wainwright.
Hi, thanks for taking my questions. Can you hear me?
Yep.
Firstly on acoramidis, 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.
Yeah, I'm happy to start on that. 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 should do better than an 84% mean max knockdown agent in terms of efficacy, and u ltimately, do better obviously than a 45% stabilizer, which is tafamidis at 80 mg. 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 the 20th most abundant protein. No one doesn't have it. In mouse models, when you eliminate it, you can see relatively severe toxicity.
If you could do all of the same things but preserve that important protein, why would you not do that? We believe that small molecules, for that reason, if they're able to deliver same or better efficacy, will be the preferred tool. As Jonathan mentioned, not everyone is going to respond to a single agent, but w e 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. Whatever 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.
Great. Go ahead.
No, 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, non-invasive diagnostic algorithm in place, and there's a lot of excitement in the general cardiology community, i t's been pretty frustrating for a lot of heart failure doctors taking care of people with progressive disease with an otherwise unspecified etiology. 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.
If you look at some of the other therapies for heart failure, the cardiology community's 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 quite a big advance. And the excitement is being energized by now that there are, in fact, treatments coming online, including as we hope acoramidis 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, 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 do you expect one to potentially out-compete or elbow out the other versus, 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. Yeah, no, look, I'll say at the outset, I don't think that there will be patients who take some of the CRF antagonists who well may end up on gene therapy. There may even be room in some patients, given that, as Jonathan said, no patient responds exactly the same as any other patient to a given drug. There may be patients who end up on both gene therapy as well as a CRF antagonist. I think the most likely thing is you're going to see uptake of the CRF antagonist until the time that gene therapy reaches the broadest marketplace. When we speak to KOLs, when we speak to patients about this, everybody sees the CRF antagonist as largely incremental change here.
Yes, you've seen reductions in 17-OHP, you've seen reductions in A4, t hey're both in phase III now, and so i t remains to be seen whether that translates to any reduction in the exogenous steroids that the patients take. But I think the thing that the CRF antagonists, even if they show some modest reduction in exogenous steroid use, they cannot allow the body to make cortisol or aldosterone. So, gene therapy is the only treatment that offers that potential, and therefore the only treatment that offers patients the opportunity to potentially completely eliminate steroids or very significantly reduce them.
Understood. The last question is for Dr. Wallace. I just wanted to see if you could comment on the competitive landscape development in the FGFR inhibitor space, particularly as this pertains to infigratinib, 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 infigratinib. Thanks.
Yeah. 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 one, in terms of efficacy, is going to be endogenous cortisol production. For that, one considers that younger population to be much more the penetrant population versus older, and it breaks out by gender as well. We're going to be probably much more used in the female population versus the male population, especially as you get older and older. We'll put forth more projections around that as we get some more data around the program. With respect to infigratinib, I think, look, number one, we were heartened by some of the data that we saw recently from Relay with their 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 access those high ORRs based on FGFR1-sparing drugs. Certainly, I didn't see anything at the recent Triple Meeting that suggested to me that the FGFR1-sparing drugs are able to whack FGFR2 and get you to a TRK-like response or something like that. They seem marginally safer in the ORR at 50%, which will likely trend down to something like 40% or less, is not that far off from what we're delivering in FGFR2 true second-line patients between us and Incyte. It's high 20s to mid-30s in terms of ORR.
I think they're going to need to do better than that in terms of ORR. My hope is that they continue to interrogate that space chemically and then we find something 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. Overall, market share-wise, it's going to take a while to develop these things. Obviously, they're going to have to come in the resistant population. 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'll be a monster market for them either.
Yeah, my hope is that they can do better for patients because an ORR in the mid-30s should be able to be surpassed with a targeted agent.
All right. Thank you.
Thanks, Raghuram. 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 Dr. 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 w ould you know how to run a trial?
We actually have recently presented data that the protein is indeed getting to the dermal epidermal layer. That is one of the endpoints we are following in the study. We can share the poster with you where we show the actual histos. You can see the fluorescently labeling C7 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.
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've already seen in the immunohistochemistry that the protein is indeed reaching the dermal epidermal junction.
Okay, got it. 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, yeah. I think that's something we're interrogating now. I think that, c ertainly, cancer cells are more perfect versions of ourselves and are extremely smart and are always trying to adapt and overcome the pressure of inhibition. If you can do that simply by expressing the active target, I think you could rapidly generate resistance to an only inactive-based inhibitor. I think that has been a mechanism that has been postulated by others in the field. 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 clonogenic assay.
Great. That's perfect. Thank you very much.
You're welcome. We'll go next to Greco, who I believe is on for Mani from Leerink.
Hi. Thanks for the deep dive on the pipeline and taking our questions. I have two questions, one on acoramidis and the other on KRAS, and we'll start with acoramidis. 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 B 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 h ow are you guys positioned for that risk versus some of the RNAi studies that began dosing later than ATTRibute?
Sorry.
Do you want to go to the second question first, or should we get started?
Oh, yeah. I can go to the second question, too. It's on KRAS, maybe focusing more on the clinical efficacy, although I know it's still early, but h ow 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.
Great. Thanks, Greco.
Hi, it's Jonathan. On acoramidis, 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 III enrollment. I think everyone on the call here is familiar with the pharmacoeconomics of the situation in the U.S., at least, that this is largely a Medicare population. There is the financial burden on a lot of patients who can't afford their co-pays. So, the people who enrolled in the U.S., 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 we have seen some drop-ins, but e lsewhere in the world where we enrolled most of the trial, tafamidis is still not widely available or reimbursed, especially in places like the U.K., Spain, and Italy. 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 tafamidis through their national health systems or through whatever reimbursement mechanisms operate in their region or in their country. We've accounted for that by modeling what the drop-in could look like over time. Two things risk mitigate against too much of a dilution in the efficacy signal. One is that we did over-enroll the trial from our original target of 510 to 632.
We also have, 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 ATTR-ACT trial, so t he later people drop in, the less impact it should have on the overall result.
Great. Eli, can we turn it to you for the KRAS landscape question?
Yeah. Thanks for that. It is early days, as you mentioned in your question. I think the way you'll start is in the refractory resistant population to current inactive G12C inhibitors. I think if you see a roughly 30% response rate in that population, that would be quite exciting. Of course, many in the field believe that the inactive inhibitors, they're certainly a great step forward for patients, but they're not seeing the responses that you see with other targeted agents, whether that's TRK or ALK or these others. We're hopeful, of course, we have to show this, that in the earlier line studies, an inhibitor that, a small molecule that can inhibit both the active and inactive form can give those types of responses to patients in earlier lines. I think you would start in the refractory setting and shoot for roughly 30%.
Of course, it's quite early [audio distortion], 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 take that as the last one.
All right. Thanks, guys. Thanks for getting me on here. Just maybe two easy ones from me. Regarding the upcoming readout of acoramidis at a 12-month time point, we've gotten a lot of questions 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, could be predicated solely on the outcomes of the six-minute walk distance test, or you would need potentially statistic outcome at month 12 on cardiovascular hospitalization rates. Then, the second one, fairly easy too, is do you think there's going to be a different mix of patient genotypes for ATTR mutants within the study relative to ATTR-ACT? Specifically, have been asked about Val122 as it relates to differences in genotype prevalence between the U.S. and ex-U.S. Thank you.
Hi, it's Jonathan Fox again. In terms of the 12-month readout, it will be restricted to a primary of change in six-minute walk distance from baseline, and a secondary of the quality of life as assessed by the overall score on the KCCQ. We will not be analyzing CVH at the 12-month time point, t hat's not part of the statistical analysis plan. That's not what was agreed with the regulatory authorities. If we hit our p- value, we'll file, t hat's our plan. 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 fairly good sampling of T60A, the so-called Appalachian or Scots-Irish variant.
We do have a lot of participants in the U.K., where there's also a mix of V122I and T60A predominantly, some V30Ms as well from people who came, migrated more from Southwestern Europe. Then, as you move through 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, you want to wrap it up?
No, I just wanted to thank everyone for spending some time with us this morning. 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.