BridgeBio Pharma, Inc. (BBIO) Earnings Call Transcript
September 9, 2020
Earnings Call Speaker Segments
Hello, and welcome to our panel discussion on TTR amyloidosis. Now I'm really pleased that we kind of have a better group of panelists here today. From Alnylam, we have Eric Green, he's the senior Vice President and General Manager of the TTR program. Next, we have Neil Kumar, CEO of both BridgeBio and its subsidiary, Ionis therapeutics; and from Ionis, we have Brett Monia, CEO. So first for our listeners, I'd like to point out that each of these companies has a deep pipeline that goes far beyond TTR amyloidosis. On this, certainly worth taking a look at but for today, we'll keep the discussions focused on TTR. So with that in mind, could each of you give an overview of your TTR programs? Perhaps let's start with Neil.
Yes. Sure. Well, first of all, thanks for being on this panel, Joel, and it's great to see colleagues here all working on the same big unmet need. I'll give a quick overview of what we're doing. We've got a small molecule program. Actually, it's a small molecule stabilizer program. And it's really focused on trying to learn from the human clinical genetics in this disease space, as everyone's here. As you well know, Joel, and have written about all of the mutations that drive hereditary form of this disease, do the same thing, which is that they stabilize this transthyretin protein. And rescue mutations that's semi effective in R104 and the other that's very effective in the T119M, Transthyretin Stabilizing Mutation that rescue disease in the context of pathogenic variants. So what we focused on were a set of design principles that really try to copy how genetics rescues people from the disease, which is restabilization at the destabilized tetramer. And we thought about 3 different design criteria. The first is we wanted to provide patients with maximal amounts of stabilization because every time we've done better in terms of stabilizing the tetramer and decreasing the amount of toxic monomer, we do better for patients. That's been shown both from the human clinical genetics as well as in polyneuropathy trials and most recently in the dose response, we see with tafamidis between 20 and 80 mg, as you pointed out. So that was the first design criteria. The second design criteria was all else being equal, we want to keep the tetramer around. This is a protein that's never not around in humans. There's no affluent [indiscernible] in all humans. Every time we've knocked it down in the context of cardiomyopathy, they are being certain in cardiac toxicities. And I think the big thing for us is that serum TTR levels correlate with human health. Certainly, they're the most predictive of the integrated markers within the context of TTR cardiomyopathy on health. And so we wanted to elevate serum TTR levels with our drug. And the final piece of the design criteria was to make a drug that would be efficient, both in the context of wild-type disease as well as for the main mutations, including V122I. And so over the course of the last few years, we've demonstrated that we can near completely stabilize patients through a series of Phase I and Phase II clinical trials. And we'll see whether or not that near-complete stabilization actually ports to benefit on mortality in a 6-minute walk in our ongoing Phase III. So that's kind of an overview of what we've been up to.
Great. Thanks. Brett, could you tell us about Ionis Akcea programs?
Sure. Pleased to. And like Neil stated, very, very happy to be here, Joel. Thanks for the invitation. So we have a TTR franchise that involves 2 antisense drugs that block the production, of course, of TTR from the liver, by targeting RNA causing the degradation of the TTR RNA very selectively. TEGSEDI is first. TEGSEDI was approved in 2018 for hereditary polyneuropathy. And is doing well. It's now commercialized in more than 15 countries and more country launches are expected in -- over the coming period of time. It really demonstrated remarkable efficacy in a Phase III study in patients with hereditary polyneuropathy as well as substantial improvements in quality of life in addition to the clinical endpoints of neurological disease progression. And TEGSEDI continues to be available for patients and continues to grow, as I mentioned. Right behind TEGSEDI, we have a new generation molecule called LICA, TTR LICA. Like all of our LICAs in the clinic today, 16-or-so in clinical development, the LICA platform offers even greater convenience for patients as once a month injectable subcutaneous once -- or less frequent even. I forgot to mention that TEGSEDI is administered subcutaneously once a week, so the LICA drug now is producing -- is being used in clinical trials once a month. TEGSEDI demonstrated about 75%, 80% reductions of TTR protein in their clinical trial, the LICA is going way beyond that based on our Phase I data. And so if TTR LICA reduction really does translate to greater efficacy -- we would expect greater efficacy because we get greater TTR reductions with the LICA. This LICA medicine is now in 2 Phase III studies. It completed Phase I. It's in a cardiomyopathy outcome trial in patients with both hereditary and wild-type cardiomyopathy due to TTR amyloidosis. And it is also in a Phase III study in patients with hereditary polyneuropathy, the same indication as TEGSEDI. And both of those studies are progressing very nicely. And then thirdly, we have a number of investigator studies that are in progress, examining TEGSEDI in patients with cardiomyopathy. And now we're beginning to move some of those patients on to the LICA medicine. In fact, some of -- one of those studies has now gone well beyond 5 years, in which patients are doing very well on TEGSEDI for more than 5 years with -- went to the study with very serious cardiomyopathy due to TTR amyloidosis. They've demonstrated improvements in 6-minute walk distance, in biomarkers like NT-proBNP and also a reduction in left ventricular mass in those studies. So that bodes very well for the LICAs that are coming into clinical trials. So TEGSEDI is the first-generation molecule that's now in the market, and TTR LICA is coming right behind it for all forms of TTR amyloidosis.
And Eric, could you tell us about the Alnylam programs?
Yes. My pleasure. Again, thank you for allowing me to join this panel. It's great to be on with the other folks that are, again, as Neil mentioned, focused on TTR. And as most people probably know, a very rare disease, but quite competitive. So it's got an interesting mix of characteristics for this space. We have 2 RNAi therapeutics: ONPATTRO, approved back in August of 2018 for the treatment of the polyneuropathy of hereditary ATTR amyloidosis; and vutrisiran, which is a second-generation product that is in development, and I'll get to that in a second. Excitingly, ONPATTRO now, and we announced at our quarterly results a couple of weeks ago, is now being sold commercially in some form of fashion in over 20 countries. And we are largely taking those direct through our Alnylam subsidiaries in various countries but also through some partnerships in various smaller markets. Exciting to mention that in our last quarterly call, at the end of Q2, we had over 1,050 patients on commercial ONPATTRO worldwide. In addition to that, we have more patients on clinical studies with patisiran, still with open-label extension studies as well as our vutrisiran program. Based on some exciting exploratory data we saw in the original polyneuropathy study, the APOLLO study with patisiran, looking at some exploratory cardiac endpoints, we get confidence in the ability to impact the cardiomyopathy aspect of this disease and are exploring patisiran's utility in that patient segment through our APOLLO-B study. So that's a pivotal Phase III study, randomized, double-blind, placebo-controlled study in about 300 patients with a 12-month endpoint looking at 6-minute walk, a very important functional end point. We're actively working to enroll that study and are expecting to complete enrollment in 2021. Now vutrisiran is a second-generation product and is a -- based on our ESC GalNAc conjugate chemistry that allows for a very compelling profile. So a simple subcutaneous administration of a very low volume of product, dosed at our clinical studies at 25 milligrams once every 3 months. So that's we find would be very compelling on top of what we expect to be very similar, if not better, efficacy and safety we've seen from patisiran and ONPATTRO already. We also just last week announced that based on our Phase I data with vutrisiran and some additional pharmacodynamic modeling, the potential for biannual dosing of a 50-milligram dose, and we'll be continuing to understand how the regulatory pathways are appropriate to bring that to patients as appropriate. So I mentioned the 2 different studies in our HELIOS program, exploring vutrisiran in the various patient segments, HELIOS-A is in that patients with polyneuropathy due to hereditary ATTR amyloidosis. We completed the enrollment in that study earlier this year and are still anticipating the data readout in early 2021. And then HELIOS-B is our much larger study to potentially expand the label to the cardiomyopathy of both hereditary and wild-type ATTR amyloidosis. That's a 600 patient study that we are actively working to enroll with a composite endpoint of all-cause mortality and recurrent CV events that is assessed after the last patient has completed 30 months on study.
Great. So thanks all of you for the overviews. And I'd like to jump into a question on clinical development. Can you tell us about the level of knockdown or stabilization that you're seeing with your agents? And the importance of the level that you're seeking? And how it compares to what's on the market right now in -- for ATTR-CM, which would be tafamidis? And I'll throw out to any of you to begin.
I'm happy to jump in there, Joel. So our -- in our Phase III study, which, again -- with TEGSEDI, which again produced remarkable efficacy hitting all those primary endpoints with high, high statistical significance. In polyneuropathy patients, we reached about 75% to 80% reductions of TTR. With a follow-on LICA medicine that I referred to earlier, we're going well beyond that, greater than 90% reductions with the dose that we selected for Phase III. And it's -- the reductions we saw in Phase I are -- were highly reproducible and very consistent with all the other LICA medicines we have in the clinic today. So we know how to dose these drugs. We know what their profile is going to look like. We know their safety and their tolerability is going to be very attractive for these drugs. And they're being dosed with a very low volume, once-a-month injection as well. I think it's really hard to compare mechanisms between a stabilizer and a knockdown. So I don't think that there's any compelling data, any real data out there that would allow you to extrapolate between the level of stabilization of a tetramer and how that equates to the level of knockdown of a disease-causing protein. What we do know is the only Phase III data out there for a stabilizer in polyneuropathy, tafamidis in its primary endpoints. And certainly, there are better stabilizers that appear to be coming down the pipe. But the knockdown approach was dramatically more efficacious than the stabilization approach, at least in polyneuropathy. The cardiomyopathy data that Pfizer showed for tafamidis was exciting. It's very, very exciting for patients with cardiomyopathy, especially wild types as there are no treatments available for it. But we -- and I only still believe that blocking the production of a disease-causing protein is going to be highly attractive from an efficacy standpoint than compared to stabilizing molecule that's already causing the disease, but we'll see, we'll see what the data it has to read out.
Okay. Yes, I'm happy to go next. I agree with some, not all of -- almost just positive. So a couple of things. One is the -- our best understanding of the pathophysiology of this disease is that it's the unfolded monomer concentrations that one needs to regulate. You can do it by knocking down TTR, you can do it by stabilizing. If one looks at the polyneuropathy channel, it's true that tafamidis was the weakest performer at about a 45% stabilization rate. And then if you move from there to the clinical data associated with diflunisal, which is about a 70% stabilizer. It was pretty close to actually what Ionis delivered in the clinic and then Alnylam with the superior data, yet still in terms of the polyneuropathy channel. And so every time we do a little bit better in decreasing the amount of unfolded monomer, we seem to do better for these patients. And like I said, you've also seen that now in the cardiomyopathy channel, our assumption is that stabilizing this to its -- to the best degree possible, which is effectively 90% at CMAn and 95-plus percent at C average is really the way to go. That's very analogous to what T119M is doing. It's increasing the transition energy state by about 40 fold. And so that you're decreasing the amount of unfolded monomer to the point at which it's been proteostatically cleared. And that to us is the optimal amount of stabilization, which is about double of what tafamidis is getting at 80 mg.
And with patisiran, we saw in the APOLLO study, a very rapid reduction of TTR in the serum after just a single dose, so at 3 weeks. And then that reduction was maintained at about mean max average of 88% for the full 18 months of that study. For vutrisiran, we have Phase I single-dose data that we've published and talked about previously. At our 25-milligram dose that were studied in the clinic, we got 83% after a single injection that was maintained for 90 days into our pharmacodynamic modeling, and we expect actually that will increase -- if you will, decrease the amount of TTR circulating to about 90% or a little more in most patients. So we expect similar to Brett mentioned, we showed the analysis with our APOLLO results with a greater TTR knockdown in the population where you see a better response or an improvement in the mNIS+7 score, so reduction of the polyneuropathy. I would agree that there's a difficulty of comparing MOA, but I also think of the disease cascade and the original treatment for this disease back from the day was liver transplant, right? Remove the offending liver that was producing the mutant or more likely to be unstable TTR, and then you saw some benefits in patients. Now problem with liver transplant is obviously the associated morbidity that comes with that very complicated procedure, but also the new liver is producing wild-type TTR. And you do see progression in those patients that have had a liver transplant as the wild-type TTR continues to be produced and lays down on existing amyloid plaque. So with our RNAi products, both patisiran and vutrisiran, we target a conserved area of the gene so that we do reduce both wild-type and any mutant TTR production. And we think that is still the best way to treat the disease.
Great. Thanks, everyone. So it appears that there'll be several agents that reach the market. Can you tell me a little bit about how -- commercially how patients and physicians may ultimately choose between agents? Are there going to be a particular endpoints for clinical trials that are particularly important to patients, providers, payers as well as any other aspects of the profiles of the drugs?
Yes, I'm happy to jump in first on this one. I think all those things you mentioned will be important to various people, stakeholders at any given time. So I think the great thing for patients with ATTR amyloidosis now is the rapid expansion of therapeutic options, both proved very recently and in development. It's great for patients to have these options. I think our fundamental belief is though most patients are going to want to drive for efficacy first, right? They want something a product that will work for them that will help them manage this progressive and debilitating disease that is relentless without treatment. So I think they want something that can best treat the disease and help them feel better, get better, at least not get as bad as past. I think after that, all things equal, safety will be very important, right? It's a very, very bad disease. Patients and physicians will be willing to accept some safety risk, but there's going to be limits to that. I mean, obviously, the safest product will be very beneficial. Safety and efficacy equal, I think then convenience to the payers, to the physicians, to the patients, in particular, may then become more important. And I think with the development of these next-generation products, patients will have lots of choices to be able to manage their life and their disease as they feel appropriate.
Yes, and I totally...
Go -- go ahead, Neil, please.
I was just going to say, I totally agree with all of that. I think efficacy is going to win as it does in many of these types of markets with a devastating disease. And within efficacy, I think mortality benefit is going to be the thing that people really focus on. And then you step from rehospitalization and step from there to 6-minute walk. So I think all of that is true. And then after that, it will be safety. And after that, it will be convenience. I think what's exciting about what's happening in the field right now for all of us is that we're identifying this disease earlier and earlier. And I think that what is going to be interesting for all of these modalities is how they are effective in earlier and earlier population. So you're going to be taking these drugs chronically for a long time, and you could stave off, hopefully, even the progression from Class I to Class II heart failure. So -- and I think we're seeing hints that if we pick it up earlier and we cease the production of these toxic monomers, we might actually even be able to see some remodeling. So -- which has been true in a lot of other cardiovascular diseases. So I think that's the exciting future. And I think the agent that allows one to go earlier and earlier could be one that is quite interesting.
And I agree as well. It's really great that there will be so many options available for patients to allow physicians and patients to choose, which is best suited for them. And I also agree that efficacy will win. At the end of the day, it will be most important. These are lethal diseases. And I think I agree with the Eric that convenience is down on the list. And the other thing is that at some point, the convenience of a once-a-month, there are less frequent, even less than once-a-month injectable starts -- the returns on that become diminishing at some point. I mean, at some point, it's really the convenience of a once-a-month or injectable versus an oral, in my view, or even less frequent subcu diminishes because you can only get so convenient. What's really going to drive these prescriptions being written is going to be the efficacy and the safety overall, I believe. I also believe that having these options available or opportunities for combination treatment. We're already seeing it. TEGSEDI on the market today is being used with tafamidis. And we -- and tafamidis' loss of exclusivity is coming up fast, and it's going to make the hurdles for combination of a drug like tafamidis with RNA-silencing mechanism even lower. So I think that those opportunities really do present themselves with additional options for patients and physicians. But at the end of the day, it's all about efficacy and it's great that there's options available.
Yes. Great points, everyone.
Maybe just to elaborate on that for a moment. I do think -- well, it's good that we think a little bit about the path of biology when you think about combinations, put aside the fact that I think it's going to be pretty damn unaffordable to use 2 of these medicines at the same time. But if you're able to knock down 95% of the tetramer or you can stabilize 95% of the tetramer such that it does not come apart from it's tetrameric state, there is no point in combination. There's no point, unless there's some other molecule physiology that I'm not aware of. So that's point number one. I think that we should be cognizant for a weak stabilizer or a weak knockdown agent, combinations may make sense. But I think in the long run, given the potency that everyone's discussing here, should be able to achieve optimal efficacy with one agent. Second thing, just to remind everyone, is LOE for tafamidis is 2029, absent any sort of extension around manufacturing or the meglumine also. It's coming, but there'll be a decade almost of competitive -- on brand medication here.
Got it. Does anyone else have any additional thoughts to add on combination therapy?
I liked what Brett says. In the U.S., in particular, we are seeing a dynamic where both agents, tafamidis and patisiran, ONPATTRO are being prescribed and are being reimbursed. Ex-U.S., other markets where they have unwillingness or unability to pay for the combination, we see a lot more switching dynamics. In Europe, tafamidis is approved for Stage I polyneuropathy of the hereditary form of the disease for almost a decade now. Physicians have a lot of experience with that. They understand the efficiencies of tafamidis for the treatment of their patients and in the space of this progressive disease. And the dynamics are a little bit different in each of the markets. So the U.S., a little bit more concomitant use we expect and see now, and we expect that to grow. But Neil has a good point, as a system, as the number of these patients are identified and eventually choose to get under treatment, it will be an increasingly large burden on the health care system.
And I also agree with Neil's point about, at some point, whether or not stable -- 95% stabilization, whether or not knockdown will give you added benefit or vice versa, with 95% knockdown whether or not you need a stabilizer. But I think biology is more complicated than that. I really -- we know that some patients in our Phase III study for neuro TTR did -- got better. They actually improved with lower reductions in TTR compared to some other patients that had greater reductions who just had disease simply stabilized. And to think that every patient will respond to a stabilizer or an RNA therapeutic, exactly the same just because the reductions are the same, I think it's too simple. I think patients are going to go on these drugs, and they're going to see how they're doing, then they're going to say, well, I think I can do better. And they're going to go on to additional drugs, if they need to because the biology is complicated, especially for TTR amyloidosis, where there's no animal models to study this disease. We're studying it in humans. And we're figuring it out as we go.
Great. A lot of great points there from everyone. And I guess we're thinking about tafamidis future in clinical trials. Given that it's already on the market, I think each of you are handling it maybe a little bit differently. Could you explain the decision or how you allow for tafamidis and your maybe TTR cardiovascular outcomes trial or other trials? And explain the decision for that.
Sure. I'll go first. So the cardiovascular outcome trial that we have in progress now with our -- like a follow-on drug, it's estimated, we're targeting about 750 patients with wild-type and hereditary cardiomyopathy and the primary endpoints are all-cause mortality and cardiovascular hospitalization. But of course, there'll be functional endpoints in that study as well that we'll be looking at very carefully. We chose to pursue what I refer to as a real-world sort of setting that patients are allowed to take standard of care. Depending on what's prescribed in that geography and what the physician prescribes to the patient, what's approved in that geography and what the physician prescribes for a patient to be used in the study, placebo or on our drug. That would be tafamidis and a lot of people in the U.S. will be on tafamidis in the cardiomyopathy service. It's approved here. And there'll be other areas where it be less so around the world. We, of course, will stratify the study so that we have a good balance of patients on tafamidis and not on tafamidis in 2 arms. But we think the advantage of that -- and we don't have a cap on the amount of tafamidis that we're allowing. We think it provides real-world data. And it will also allow us potentially -- we're hoping to be able to actually make direct comparisons and at least provide evidence of data of our LICA medicine versus tafamidis as well as the benefit of combination versus tafamidis alone, being tafamidis being in the placebo arm. So we think that there's a lot of opportunities both on the data we're going to get from the study to be able to interpret how good our drugs is versus tafamidis as well as on top of tafamidis. And -- but also, it allows patients to take drugs that are the standard of care on the market, so they can maximize their benefit in a real-world setting. And this has been very well received by investigators who helped us design the study.
I can go because our trial has been out and running for a little while. You typically get what you study, that's certainly the feedback we got from the agency. So we needed to run some form of placebo-controlled trial specifically in this population where there are multiple comorbidities. So that's why we have this massive trial design, where we were able to get going quickly enough such that we could get a part A readout on 6-minute walk before we allowed for any tafamidis drop in. That window is obviously narrowing, most of that enrollment was in Europe, and that's where tafamidis isn't right now, but will be soon. The second part of our trial was using the extension of the 12 months to go all the way to 30 months, so a delta of 18 months that does allow for tafamidis drop in, which I think is appropriate, and I think is ethical. And the one thing that we have going for us there is that tafamidis didn't separate the curves on mortality up and until about 18 months in the trial, maybe around 15 months. And so we're powered to be able to discriminate a signal in the context of tafamidis background there. But that's how we've approached the trial. I think it's going to be increasingly obviously difficult to run placebo-controlled trials in the marketplace as tafamidis gains more and more access worldwide.
And similar strategies for us that we do have the 2 studies in the cardiomyopathy population. So with patisiran in our APOLLO-B study, we actually have a 30% cap on patients coming in to the study on tafamidis already. We have further requirements that we'd prefer them to be on. They need to be on at least 6 months on tafamidis and per the physician's discretion, some sort of progression. That's important for us with APOLLO-B. It's only a 12-month study, placebo-controlled, so relatively quickly and agree with Neil, the data we saw and analyzed from the track data, the benefit of tafamidis may be somewhat late onset. So we felt that was the best way to allow for enrollment broadly globally in APOLLO-B, but also protract the power of the small study of 300 patients. For HELIOS-B, our larger study, the 600 patient study, with vutrisiran, we still have a 30% cap on patients entering with tafamidis, though no requirements for a certain minimum amount of time or progression on tafamidis. And again, we felt this is necessary to recognize the reality of the market with tafamidis now getting approved a year, 1.5 years ago in some markets but also the fact that access is uniform. Even if it's approved in some countries, they do not yet have pricing or reimbursement through their insurance companies or health -- their governments. And indeed, even in countries where pricing and reimbursement is technically allowed or approved, there's still access concerns. Even here in the U.S., there are patients that cannot afford to be on tafamidis. And therefore, I think these studies from all of our companies actually offers them an opportunity if they're not able to take advantage of a commercial product. So we feel that operationally, going around the globe is beneficial to get the full mix of the type of patients you would see with this disease, both on the mutation side, but more importantly, in the wild type. So operationally, it's about going to all the areas to find these patients, still a relatively rare and less diagnosed product -- disease, it's important for us to operationalize.
Great. Thanks, everyone, for that. Another question on clinical trials. That's a hard question now a days in general. Just how has COVID-19 impacted the ongoing clinical development and enrollment?
We had the fortune of the HELIOS-A study, so vutrisiran study in the polyneuropathy population had completed enrollment earlier this year, just weeks before when COVID really hit the U.S. and in other countries around the world. So we're fortunate that enrollment had completed in that study. And now our teams have really been focused on with our sites and our patients is continuing to get them treatment, making sure they meet their doses or HELIOS-A, and this is where it's important and I think beneficial to have a less frequent dosing regimen. So once every 3 months subcutaneous is much easier to manage than trying to get in for a more frequent infusion or injection during the clinical study. And then, of course, we're obviously focusing on making sure they get there for their final assessments, and the best extent we can, the data quality. As health care systems and individual sites and hospitals have actually shut down, most of them are reopening, but it obviously varies around the world. For our 2 cardiomyopathy studies, we had just started enrollment. So we get hit as most other companies did. Saw a dramatic slowdown in enrollment, but we continue to background working on activating sites as appropriate and necessary remotely. And we've actually seen a very nice return to enrollment in both of our B studies, the APOLLO-B and HELIOS-B, as more and more countries are getting to handle on COVID, or at least the health care systems are able to focus on things beyond just the treatment of the pandemic.
Yes. I'd extend that. I mean we took a delay in March and April, it has come roaring back. In part, this is a devastating disease, as everyone has mentioned here. And in part, it's a real testament to the physicians and the bravery and the courage of the patients. We've been mailing drug home. We've been ensuring that everyone who was getting drug, continue to get drug and now our 100-plus sites across the world, you're seeing quite a bit of interest in the trial. So yes. It's obviously a significant concern when you talk about a relatively older patient population with cardiovascular disease. But I think it does, again, speak to the severity of this disease that people have wanted to come. In fact, bridge, we run quite a few, just as the rest of these folks do, clinical trials. And you can see the discriminatory nature of COVID. When it's a severe unmet need, people are finding a way to access a health care system and certainly, this is one of those severe unmet need stuff.
And our experience has been very similar. There's been some impact early on in the Phase III studies. On getting sites -- certain sites activated, particularly in areas that were hit the hardest with COVID at the time we were activating those sites. We've been working with these sites remotely and getting them up and running. We're pretty much past it now. So there was some impact on site activation, and on enrollment for the 2 Phase III studies, polyneuropathy and cardiomyopathy, but there's plenty of time to catch up and -- in these studies. And we feel pretty good where we are with the enrollment so far. As we said, there is a strong desire for these drugs for patients and physicians. And although the impact -- there's been some impact, I think it's been -- we're managing through it very well.
Great. Thanks, everyone. So I'd like to switch gears a little bit and talk about the market size. There seems to be varying estimates out there of how large TTR amyloidosis is, I mean. But before our rare disease, it seems to be on the large side, and we've seen the rate of diagnosis seeming to increase pretty steadily in polyneuropathy and cardiomyopathy as drugs have come in the market. So is there any more information that you could share or sources of information or perspectives on how large the market opportunity could be?
Okay. So I think -- sorry. Consistent, I think, across all of our companies, it's always hard to know in a rare disease. And usually, as you start looking, you start finding more and that's been proven over and over in these rare diseases. We believe the hereditary market possible global prevalence of around 50,000 patients. That's a number that's been around for quite a while, and I think we'll continue to look for all 50,000 of those patients until the end of our careers, I'm sure. On the wild-type side, I think the estimates are much more varied and harder to come by. We believe there's around 200,000 to 300,000 patients in the world with wild-type disease. Obviously, probably from dominantly presenting with cardiomyopathy, but there are many physicians, KOLs and other folks that think it could be much higher. And I think it's very hard to estimate. I'd love to hear what the others say.
Yes. No, I agree completely. What's intriguing are obviously the state of reason studies that suggest that between 13% and 19% of half of that patients are actually TTR patients hiding within that population and not just necessarily quantitative contributions of destabilizing mutations or something, but the wild-type patients. So if that's true, then obviously, the population in the U.S. is hundreds of thousands. Certainly, we're nowhere close to that in terms of diagnosis. The other thing that's interesting to think about is the percent of African-Americans that have the V122I mutation and the associated penetrants, which seems to be quite low, could be the fact that we're just missing this disease in the context of many folks. And we need to do better at that. And I know everyone on this panel is committed to doing better. So I think exactly, as Eric said, we just don't know right now. The hope is that with better agents, we're going to do better, help pick these folks up. But this could be quite a large inherited disease, inherited with a side population of wild type, and that's likely because it affects people later in life. And so it's not really affecting reproductive fitness in the same way that you see with many of the other Mendelian diseases.
We're all reading the same papers, Joe. And the estimates are 200,000 to 300,000 for cardiomyopathy and maybe 50,000 for hereditary, which the majority of those hereditary patients have polyneuropathy or mixed phenotype. I do believe that the wild-type cardiomyopathy patient population is underestimated for the reasons that Neil mentioned. It's new. It's relatively recently understood -- it's a relatively recently understood disease. And it hit in other forms of cardiovascular disease that, I think, is becoming far better understood today. And we can refer to the published reports, which we should all do as good scientists. But I think our gut feeling is that it's vastly underdiagnosed, while particularly wild-type cardiomyopathy. And I think that as drugs emerge, and treatment options become available as a true for so many diseases when new treatments come out, patients come out, and they have become identified. And just the experience of having a treatment really pushes the field to identify in buying those patients who are suffering from a disease where a treatment now is available to have an impact on it.
If I may add on, I think, disease awareness is something that's driven by all of us through our development activities through the awareness and through the commercialization efforts and Pfizer certainly is helping the bat and their scale. And so -- but I've been heartened to see in conferences over the last couple of years a change where there's now entire tracks for ATTR amyloidosis, especially in the cardiology side, and have seen some pretty entertaining positions chastise their fellow cardiologists, we're not finding, this disease is there. You're missing it. You're failing your patient by not finding this. So having the physicians drive the awareness and the education has been critical and it'll augment whatever we small -- as we can do as a companies. I think the other piece that's important is the diagnostics have gotten better on the cardiology side, right? The idea of a noninvasive technetium scan that can be very sensitive and specific for ATTR amyloidosis, especially the amyloid buildup in the heart, I think could really has revolutionized how we can find these patients. As speaking with a KOL the other day, you'd rather make every heart failure patient release, every half of that patient get a technician scan to rule out ATTR amyloidosis instead of confirming the diagnosis. So that mindset is probably a minority right now, but hopefully, it changes over time.
Yes. And just to build on that. I mean, first of all, the level of excitement is, I'd say, fairly unique just because it is along with hypertrophic cardiomyopathy, one of the more interesting, I think, areas of cardiovascular medicine now. But I do think the concept of primary prevention and moving earlier in some studies that, okay, you've got carpal tunnel, maybe that's an interesting population to start technetium scanning. There are several other higher-risk populations that one might want to consider. And I think that will increase the population size, but it will also be really exciting so that we can find these patients a little earlier. So I think those study will help us to identify some of the missing patients.
Anyone have anything else to add on that? All right. So maybe I'll ask one more question from the audience before we wrap up. And the question is, our results from neuro trials generally predictive of success in cardio trials or vice versa with cardio trials success be generally predictive of success in neuro.
I don't think we have enough data to draw strong conclusions one way or another. What we do know is that the -- that there's likelihood that the underlying mechanism of neurological toxicity to TTR amyloidosis, may be different than cardiomyopathy. That is both are closed by TTR. But one is -- one promotes a restrictive cardiomyopathy due to amyloid buildup in the heart, causing the heart to fail. The mechanisms that caused destruction and peripheral nervous system, the TTR accumulation, is not as well understood. There can be toxic species that are contributing to this disease. It could be unlike buildup, destruction of surrounding tissues and cells. It's a different mechanism. With that said, we do know the cause of these 2 diseases. And if we can -- and then that includes destabilization of the tetramer. So if we can do something about the destabilization of the tetramer, or block the production here, regardless of the fact that the mechanisms that are causing a disruption of the cardiovascular peripheral nervous system may be different. I think that you have a very strong probability of being successful in that clinical trial for cardiovascular diseases that was set up by the peripheral -- by the polyneuropathy Phase II studies.
And maybe to build on that, and it's an interesting question. It's -- I can't think of a good example of -- there's certainly no historical data set that would give you a PTS there. But what is interesting to consider is well, one, protein misfolding diseases. There's plenty of protein misfolding diseases where you have difference in mutations can lead to different types of tauopathies, for instance, or has it been a drug this trial across those locations, not that I know of, successfully. Then you kind of step back and say, this is sort of like precision oncology, where you've got the same mutation, but it could occur in a couple of different tissue context and what is the predictivity of being able to target a specific driver. And I think as [ Steve Elliginor ] has published, is not 100%, but it's not bad. When you understand the underlying pathobiology of the disease and you're targeting the disease at its source, tissue context is important, but is less a descriptor than is the specific mutation. Now I'm talking about the hereditary form of the disease. So I would say it's -- I don't know, all of that to say, it's reasonably predictive, but context does matter. I don't think there's a perfect attitude to it. I don't know, Eric, what do you say?
Small data set and depressed volume. Tafamidis had a failed primary in their polyneuropathy study but went on to successful cardiomyopathy study. So I think if we all knew that answer to the correlation, we don't feel a lot more comfortable as we wait for the next several years for our clinical studies to read out, but we'll know a lot more on that very question in a couple of years.
Great. Thanks, everyone. So this has been a great panel. And with that, we've reached our time. I'd like to give a big thank you to each of the panelists for joining us. It's been a great discussion. And then also for the listeners, for more information on TTR amyloidosis, earlier this week, I published a deep dives. It is available if you'd like more information. And then also, I'd like to point you to R&D webcast from each of the companies here today. Alnylam and Ionis both had webcast last week that I found quite helpful, and BridgeBio has one scheduled for later this month. So thank you, everyone.
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