BridgeBio Pharma, Inc. (BBIO) Earnings Call Transcript & Summary

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Thanks, [ Val ]. Thanks, everyone, for joining us today. So I'm joined by BridgeBio management, Neil Kumar, Founder and CEO; and Cameron Turtle, Chief Strategy Officer at BridgeBio. So thanks for joining us today. And as you know, the top [ vehicle ] for today is one of the upcoming Phase III data for acoramidis and TTR amyloidosis cardiomyopathy.

So Neil and Cameron, maybe we can start to weigh kind of a high-level overview of a Phase III trial design and powering assumptions and then we can go into more details.

Yes, sure. Happy to kick it off, and thanks again, Eun, for the opportunity to chat today about acoramidis, and hopefully, we'll get into some other products as well. As you know, this is really going to be the flagship for hopefully our ability to build a real leading company in genetic medicine, one that's held by a multibillion-dollar franchise that can help a lot of patients like acoramidis, and with several Phase II, Phase IIIs delivering right behind it. Hopefully, we can build the type of company that's rarely built in the rare disease community. So just in terms of acoramadis, obviously, this is a nested trial design. Part A reading out at the very end of this year. Part B reading out 18 months later. The results that we're looking for in Part A, which will lead to, if positive, full approval, would be 6-minute walk distance. And then in Part B, we'd be looking at CVH and mortality. Trial was designed almost exactly the same as ATTR-ACT, which most people will be familiar with Pfizer's trial where they were interrogating tafamidis' effect on ATTR-CM patients with many of the same inclusion, exclusion criteria and ultimately, many of the same powering assumptions. In fact, we were a little conservative, as you and I have discussed in the past, on our powering assumptions, elevating the number of patients so that overenrolling the trial to ultimately get to the point where we deliver the -- even the same efficacy as tafamidis, we would expect a positive trial.

Okay. So obviously, the timing of the trial, you said Part A, is really very end of this year. So do you think there is a chance that it could actually go over to next year?

Do I think there's a chance, what, sorry?

Go over to next year or the next year?

No, probably not. I mean it's -- time lines are pretty well set right now. We have last patient last visit already. So we're in the game just in terms of database flows, database cleaning. I suppose if anything slower, we rely on a lot of third parties, and we're going to be extraordinarily careful throughout the course of this time to make sure that no one is unblinded to anything that could affect Part B since this is a nested trial design. That's our #1 priority here. So we're working with Duke, working with our vendors. But I think that -- I think you should expect it at the very end of this year will be my best guess right now.

So this is over 630-patient trial. Pretty large. I think the last patient exited already. So how long does it take to actually lock the database, clean it and then analyze the data?

A couple of months.

Couple of months.

I mean typically, that's what we found is actually a couple of months. And I think in this case, it might be a little slower as the data goes through its various -- both Duke and our third parties. But usually, it's about 2 months.

So toward the end of the year, it's a holiday season. So do you think that you could provide more narrow the timing as we get closer to the data?

Yes. I think we'll probably make an announcement as we get closer so that people can tune in as we get more clarity against the time line. But right now, that will be inappropriate, I'd say.

Okay. So Part A data coming out toward the very end of this year. So this is a 6-minute walking distance at 12 months time point. So before we get into data expectations, I want to ask you of a patient profile that we can compare to tafamidis Phase III trial. So in tafamidis Phase III, about 60% of the patients were categorized at -- as heart association Class II and about 30% was a Class III. And then when you look at the wild type versus variant, it was 75% versus about 25%. So based on that information, do you think your patient profile in the trial will be similar?

Yes. So basically, I think that, again, the trial design, inclusion/exclusion criteria, everything was basically designed to match up. We've got Class I, II, III patients as well, excluding AL. So very, very similar approach. I think the only thing that you might think about being slightly different is my best guess will be that we're going to have more wild-type patients than did Pfizer just because we're trialing a lot more in Europe. Actually, the V122I mutation is quite common in the U.K., but less common in some of the other countries where we enrolled quite a few patients. We're also finding a lot more wild-type patients now. The levels of diagnosis have increased. So I think that will be one difference. It would be my best guess. But everything else is going to be pretty similar. And I think what we publicly disclosed is that if you look at the ambulation amounts for the starting population, they're like almost dead on each other, 355 meters or so in that range. So pretty similar. I mean it's designed to be similar.

Okay. And then obviously, destabilize the TTR is the genetic driver for the condition and leading to amyloid accumulation. So better TTR stabilizer would have a better outcome. But then like when we see like in vitro data, like last week at the end of the day, in addition of the in vitro data looking at the target TTR binding site occupancy. And then your product which shows close to 100% whereas a tafamidis at 80 milligrams showed about 50% to 60%. So that's an in vitro data, but have you also looked at TTR serum levels in terms of normalization comparing like acoramidis versus tafamidis 80-milligram?

Yes. So I think just to restate what you were just saying across 4 different fairly well-validated assays, what you can see is near complete and basically complete stabilization with acoramidis versus what's a little less than 50% stabilization at 80 mg tafamidis. But those are obviously in vitro or we might consider in vitro assays, even though you're getting patient [ sera ] in many cases. We've also looked at, as you saw from our Phase II data, serum TTR levels, which obviously should elevate as you stabilize. And what we saw was about 50% increased serum TTR levels as compared to what tafamidis is able to generate a high dose. And so any measure one were to look at, I think we -- it's very clear that this molecule is going to stabilize in excess to what tafamidis can. And I think that's consistent with the biochemistry that we know, which is that you're seeing more target, that you've got a superior KD2. So you're binding more target and ultimately doing a better job of gluing the tetramer together, driving the hydrogen bonding at the bottom of the thyroxine binding pocket with a slightly more enthalpic binding mode as we published in J. Med. Chem. I think all those dots fit together pretty nicely.

At the same time, Pfizer has indicated that they are -- seem like a max TTR stabilization at 80 milligram and although your in vitro data looks different. So how can -- how -- from our perspective, how can you reconcile the difference between what you are showing with your data versus what Pfizer is saying that they are seeing close to max stabilization?

So I think that's a product of the way Pfizer has articulated their y-axis which has changed in a couple of different FDA submissions. But I don't -- like I mean -- actually, in the appendix of any GM paper -- any [ JM ] paper, in a track, you can clearly see that they're getting to about 50% stabilization as defined by any of the classic Western blot or FPE assays. I don't think Pfizer has ever come out and said against the assays that are usually used that they're getting full stabilization. If they have, that's incorrect -- scientifically incorrect. I think the most bold statement that was made was in the amyloid paper that Jeff Kelly recently put out where he compared 28 micromolar Pfizer, which is their max concentration against 11 micromolar AG10. So that was obviously a misnomer, 42 micromolars are seeing max. And if you compare those even using his plots, this is the inventor of tafamidis. What you can see is excess stabilization for AG10 that's quite marked. So I'm not sure that there's any in vitro assay that says they're fully stabilizing anything. And obviously, if serum TTR level is elevated in our -- with our drug versus their drug again in a cross-drop comparison, I'm not sure that won't get -- we could claim that either. I mean look, I think we're close to data. But one thing that is for sure is if you were getting full stabilization or close to full stabilization, because remember, there isn't that much of a difference between 20 and 80 in terms of stabilization because of the excess albumin binding that they have, 4x a dose increase only at least to about 2.5x exposure and a small amount of increased stabilization. And why on earth would diflunisal handily outperform TAF 20 polyneuropathy. So they're not 100% stabilizing anyway.

Okay. So on 6-minute walking distance at 12 months time point, didn't you say at the baseline, our patients about 350 meters similar to tafamidis. So obviously then, we could expect the decline of about 60 meters in your trial compared to -- similar to what tafamidis trial has shown. So one question -- there are a couple of questions. One is that in Pfizer's trial, about 30% -- about 1/3 of the patients were on 20-milligram dose, which is not optimal. And then they show a 25-meter decline at 12 months, whereas placebo show about 60. So do you think that had they -- had all patients on 80 milligrams, not 1/3 on 20, do you think that they are 6-minute walking distance decline would be -- I don't know. This is kind of a simplistic way, but about 1/3 less than 25 meters or at least less than 25 meters?

That's not how math works. But...

Yes.

Come on.

But at least less than 25 meters.

Yes. No, I think you can safely say that in as much as that 6-meter walk distance is connected to mortality, we know that from the [ lane ] paper, and we know that 80 outperformed 20 in terms of mortality, we don't have the exact data for 80 versus 20 in terms of 6-minute walk at 12 months, but you could assume that 80 outperformed 20 by probably some small margin. And so, yes, the patients probably would have done better if they were all -- not probably, they would have done better if they were on 80 is my assumption versus 20.

Okay. So AG10 acoramidis shows near-complete TTR stabilization. I mean isn't it reasonable to expect that it could hurt, but not just slowing the decline, but could potentially stop the progression? So that instead of expecting, hey, certain levels -- certain mirrors of a decline at 12 months time point, can we actually expect that whatever it shows, whether it's a decline or stabilization, you would be still allowed to help the population?

Well, you got to remember ATTR-CM. So yes, I think it could. And I think it will in some patients, whether or not a very sick patient with ATTR-CM is going to -- it can halt the disease at that point, one doesn't know because these are sicker patients than are healthy people who are 72 years old, obviously. So there's other things going on at that point. Yes, I think the theory of the case is that if one were able to turn down toxic monomer production to the extent that we are such that you don't get any more further deposition in the heart, that you could get come as close to possible as halting the disease. How that manifests in the actual data, if that means that some of the Class III patients continue to decline, but you catched it earlier and you may be better and better, who knows? I don't know. But for us, I think a success scenario is if we're able to deliver over 20% relative risk reduction versus where TAF was, so if it's minus 25%, if we're in the teens, then you start to feel good about, I think, a differentiation, especially if it connects up with, again, 2x the stabilization, 50% more of serum TTR elevation, outperformance on key biomarkers like BMP as we saw in our Phase II, I think all of those things will go hand in hand.

So when we support a data, we have [indiscernible] those cardiac biomarker data as well?

We may. I mean -- oh, okay, we're not.

I think the cardiac biomarkers are more likely to come in an academic presentation next year.

Academic presentation.

Okay. At the clinicaltrials.gov website and cardiac biomarkers or measure the like -- I mean I'm sure that you're measuring periodically, but a 12 -- 30 months time point is not necessarily a 12 months time point. So in terms of -- so when the data comes out, Street is going to compare your data to tafamidis data. And obviously, this is across the study comparison. So as you pointed out, if you show 6-minute walking decline in teens versus tafamidis had shown 25 meters, but it's -- given that it's a cross-study comparison, obviously, we are looking for a numerical difference. But how much a numerical difference really has to be there in order for the financial community to feel more comfortable, that, hey, AG10 is -- indeed is a better driving performance?

Well, I think the bigger thing we're focused on is what kind of difference we need to show for the physician and patient community to feel that there's a difference. And I think that's on a couple of different dimensions. Number one is I think that's why we said 20% or more relative risk reduction, which puts you into teams, unlike mortality, where the gold standard in cardiovascular disease is like 15% relative risk reduction. And I think the second thing is the ability to line up and connect the dots between what we're seeing in terms of better performance on 6-minute walk as well as better performance on serum TTR and some of these other variables that are great univariate predictors of mortality. I think if all that happens, physicians are smart enough just as they were in hypercholesterolemia and many other diseases associated with cardiovascular disease. The better you do in terms of stabilization, the better you do for patients. Put it all together, I think people will prescribe this drug.

So do you think that -- what kind of a data point do you think you would like to see in order for -- to have a confidence in that it's going to really translate into better mortality, morbidity benefit? I mean so is there kind of like a correlation between 6-minute walking distance decline versus the cardiovascular outcome part of it?

Yes, there is. The [ lane ] paper lays all of that out. There's actually a couple of different papers, but the best is the [ laying it all ] paper, which I think was published, I don't know, a year or 2 ago, that lays out the differences in 6-minute walk as they correlate with hazard ratios. But yes, there's a good predictive element there. There's a good predictive element with serum TTR levels as well. So yes, I think both of those would be interesting to look at the end.

But is there like a -- it's a real speculative. But is there a certain level of 6-minute walking distance you want to see to -- decline that you want to see in order to have a confidence that, hey, on the mortality, morbidity benefits, our drug would be better than tafamidis?

Oh yes. I think -- well, I think -- yes. I think if you're talking about something like 8 to 10 meters in terms of a delta, you could expect that, that -- first of all, a 12-month difference is going to be exaggerated at 30 months. We know that because he's right -- I mean that's obvious. So if you're talking about even an 8-meter difference, putting you in the teens, obviously. But in the high teens, I think that would -- ultimately, if you look at that delta, correlate with a meaningful difference in mortality. And I think also if you continue to see 50% elevation levels or 30%, 40%, 50% elevation levels of serum TTR, that would also correlate meaningfully with a greater than 15% relative decrease in mortality. I mean just remember that when we looked at the difference in stabilization between 20 and 80, just 37% to a little under 50%, you had a 20% relative risk reduction between the 20 and 80 mg groups. So phenomenal risk reduction between those 2. And so I think that -- I think you could expect to see something pretty meaningful if you were able to drop 6-minute walk by 8 meters. Also, that's meaningful for patients. I mean the ability to walk 10 meters is a big deal for people going to dance with your grandkids or going to get your mail or whatever. So these are typically healthy people until they get ATTR-CM. So it's a big disease, a big deal in and of itself.

So to summarize your expectations, I don't want to put words into your mouth, but it seems like acoramidis, assuming that the placebo decline similarly as the tafamidis Phase III trial, which is about 60 meters, you would expect with acoramidis at 12 months around 15-, 17-meter decline? Is that...

Yes. I think in the teens is appropriate. Yes. I think starting -- like starting with the populations we're starting at, I think if we don't hit the teens, I'm not sure that we can say that we're better. Yes.

Okay. Okay. And then in terms of a trial, like a patient profile seems really similar except for the fact that you may have even wilder-type patients [indiscernible]?

Yes. Which is natural given the evolution of how we're diagnosing the disease and also the countries where we were in.

When you look at your earlier data, the acoramidis is pretty potent against the variant. So do you think having more [indiscernible] wilder-type patient might have some impact on the outcome or it's too negligible?

We didn't see a significant difference in that in ATTR-ACT between the mutant and the wild-type populations and went with potent. I mean so I feel pretty good about our chances in mutant and wild type as well. It's not like we're not hitting wild type.

But how about on the placebo side?

[indiscernible] similarly set. I know people generally think that a [indiscernible] form is sicker, but that's not the case as far as we can tell on ATTR-ACT. I don't know. What were you saying, Cameron?

I was just going to say that the treatment effect size on both mortality and 6-minute walk was almost identical in ATTR-ACT between the variant population and the wild-type population. So that's our base case assumption for our study as well. Though in going, we did have some of the expectation you're alluding to, which is that you do see a greater increase in serum TTR levels for individuals on acoramadis and in -- for variant patients than those with wild type, and that's because they start with a less stable form of TTR and you raise everybody up to near complete stabilization. So we think it could or should be possible to see a greater effect size there. That just isn't what we're seeing in ATTR-ACT. And so we don't have that expectation going in.

Okay. So the one big difference that I see between your trial and Pfizer's trial is really the number of patients. If I calculate correctly, I mean if my math is correct, you have like about 40% greater [indiscernible] patients in your trial. So that's very overpowered. So within that kind of powering assumptions, I mean it's highly unlikely that, that is going to miss the end point because placebo performed a little than whatever. But given they have a larger patients, do you think that data points could be tighter so that they could actually help in terms of like numerical numbers difference in your trial compared to tafamidis or you don't think that's going to impact much at all? You know what I was saying?

I mean the standard error given that [indiscernible] is in the denominator, it will be tighter. If you're sampling the same distribution but with more end, then yes, I guess the standard error would be tighter. But...

So question is the data points are tighter. So in a way that when you present the data in aggregate, in average, it could actually show better outcome?

No, because -- I mean standard error would be tighter to your point, but the mean is the mean of the distribution that you're sampling. So ultimately, it's not going to take the number from 18, 15. It's going to be 18 with a little more confidence, which is exactly why you just said that trial's powered -- that it's powered better, too. That's all you would see, but you would still see the same number. You'd see the number of deliveries. I mean if tafamidis ran twice the number of patients, the theory of the case would be that they still get the same means, just different standard error, right?

So what was your reason behind like increasing the number of patients by 40% compared to...

Well, we started it -- we started with a target of 510 because it was COVID. And we were afraid that we would have a higher discontinuity rate, and ultimately, we ended up having. And then once you have -- the trial enrolls like a hockey stick. And at the very end, we brought on a number of new sites, and it felt pretty unethical just to say like we're not going to let these patients on. Remember that most of the geographies that we were running in, by virtue of the fact that tafamidis was approved already, were geographies that didn't have access to tafamidis, mostly in Europe. And so it didn't feel right to us to not allow those patients on the trial. We didn't think that there was much downside. And also just in terms of commercial seating, I think it's important for us to be running a trial that affects as many sites as possible.

Okay. So another thing that you said was that Part A is a successful [indiscernible] approval in the U.S. and Europe by mid-2022, and they could lead to full approval. So question to you is that tafamidis was approved based on the clinical outcomes, like morbidity and mortality. And then from your discussions with the regulators, they are allowing you to file based on the 6-minute walking distance. So can you elaborate on the discussions? And why do you think regulators will allow you to 5- or 6-minute walking distance whereas they approved the tafamidis on clinical outcomes?

Well, the regulatory agencies have always been clear about what constitutes an approvable full end point, which is obviously making patients feel better or demonstrating that they die less on therapy and 6-minute walk is a tried and true full approvable end point. In this case, the agency actually worked with us to identify 6-minute walk as a trialable end point, not unlike they must have with Alnylam because Alnylam is obviously running a trial that only has 6-minute walk as an end point, and they expect full approval of that. We're obviously moving on to also get mortality data. But yes, I mean I think we basically had that conversation with the cardiorenal division, and we've had that conversation into Europe, and we're pretty confident that we'll be able to follow on that. It's not like a biomarker like oxalate reduction or something in one of our trials. It's a true functional end point.

Okay. So what happens -- so -- okay. So is there any kind of like a 6-minute walking distance data you would need to show or there's a p-value of less than 0.01?

Yes. P-value of less than 0.01. Yes.

Okay. All right. So do you expect a standard review from -- for review at the FDA once you have approval?

Yes. And we would expect that we would use our PRV as well.

Okay. All right. So by the time drug gets approved, you would have a Part B data, which you...

Yes. I mean if we really hustle it out, it'd be early 2023 where we launch and we get the Part B data just shortly after that, a few months after. Yes.

Okay. So in Part B, so 12 months, patients are on acoramidis versus placebo, but after 12 months, physicians can actually utilize the tafamidis, right, after 30 months. So can you kind of comment on what percent of patients after 12 months would have gotten tafamidis?

Yes. I mean that's a product of how quickly tafamidis gains access in the geographies where we're trialing, right? I mean tafamidis isn't accessible right now in the U.K. and in broad swaths of Europe. So my assumption would be as they become accessible, we see a lot of drop on. I mean we obviously have a lot of patients right now that have gone past 12 months. And most of those patients aren't on tafamidis. Because either in the U.S., they access our trial because they couldn't forward tafamidis, or in Europe, they access our trial because tafamidis wasn't on market, and it's taking a little while for them to get on market. So I don't know what the percent will be. Certainly, we designed the trial such that tafamidis -- the defective tafamidis on mortality and CVH would be minimal because you don't see a KM curve separate up and until 15 months or so as a minimal separation at 18 months. And so that I don't -- so yes, but I can't comment on the percent.

Okay. So when physicians are allowed to utilize the tafamidis, can they actually add a tafamidis on top of acoramidis? Or is it only for placebo patients?

No, it's a blinded trial. Yes, they can add it on top. Yes.

All right. But do you think the addition will make a difference?

No. Because we've shown biochemically that acoramidis displace tafamidis. And so I don't -- it's not like it's a 2 separate binding sites, and there would be some additive effect there. I don't think you would expect to see anything out of that.

Okay. So in Pfizer ATTR-ACT trial, tafamidis, the 30-month mortality rate was close to 30%. I think the placebo was about over 40%, about 43%. So when you look at those score, that only shows about 30%. So what do you think you would need to show in order to -- medical [ treated ] patient on a [ worse ] rate to actually look at it, hey, acoramidis is better in terms of controlling hospitalization, death and things like that?

I mean I think in that 25% range, 15% relative risk reduction, that math right is where we'd want to be. And I think that if we had that again, connecting the dots to a better 6-minute walk, can I take the [ dose ] to a better [ serum ] TTR and a superior stabilization, that would be a resounding victory.

Okay. So we want to get in the commercial strategy. So obviously, you guys are fully developing the product. Knowing that it's a better drug than tafamidis. So when the data comes out, it's numerically clearly better and there is no question. But what if it's kind of like a similar, let's say, 6-minute walk distance, it's better. But then somehow on the mortality, morbidity benefit, it wasn't really that much different. How do that change your commercial strategy?

Yes, great question. I mean I think that obviously, we've designed the therapy to be a best-in-class therapy. If it's effectively a me-too or viewed by physicians as a me-too, it changes a couple of elements of the strategy. I'd say, first and foremost, it would change our access strategy, where we'd be very focused on talking to payers about what they need to see from us in terms of contracting, rebating, et cetera, to be 1 of 2 since we're coming later to the market, probably change elements of the way that we do distribution. And that also would -- if we continue to believe that we were superior, like in the case where you just said, 6-minute walk laid out but somehow it didn't play out in mortality, I think it would completely change Phase IV strategy, where right now, we're very focused on primary prevention and trying to understand how to move this therapy as early as possible in the mass action disease. I think we'd want to follow up with clinical studies to understand if there are subpopulations or areas where we have superiority, where a better stabilizer ultimately does deliver superior efficacy. So those would be the obvious places that it would change. I don't know, Cameron, if you'd add anything there?

No, I think that's pretty comprehensive.

So in the U.S. and Europe, you are planning to launch on your own. And then in Japan, you have with AstraZeneca. How about the rest of the world, what's your strategy for that?

Well, I think Latin America is a very attractive market. We are there in terms of clinical trials. And I think places like Brazil and Colombia offered to a company an interesting place to build. And I think we can build there not only for the franchise, but others of our franchises so that I would expect that we could do something maybe early with the distributor, but ultimately, hopefully build our own infrastructure there. China is an open question for us. Still, we continue to evaluate. First of all, it'd be interesting to see how tafamidis, if they get a clinical trial waiver, if they're able to come onto the market, what kind of the uptake is there, that will -- we'll be watching that with interest. But I think that remains a very interesting marketplace for us. Beyond that, I think we would access distributors or local partners.

How about -- the acoramidis is twice daily while tafamidis is once daily, does that kind of play into pricing strategy?

How so?

Well, obviously, once daily is a lot more convenient than twice daily. No?

Well, first of all, these are 72-year-old pretty sick patients who are used to taking pills morning and night, but I don't think convenience once versus twice daily pills is what's going to drive market share for a disease that's killing 42% of people over 30 months. I think it's ultimately going to be efficacy. If you're talking about the construct under which we're the same as tafamidis, maybe that's one thing that might drive tafamidis market share. Pricing will be a tight wire if we're the same because as I just mentioned, you're going to have to rebate in the U.S., so you're going to have to keep the price high enough so you can do that. But you're going to have to think about, obviously something competitive in Europe so that you can get on.

So tafamidis has been in the market over 2 years. And have you heard what the kind of compliance rate there?

Compliance rates are high from what we've seen, what we've been able to observe. Obviously, there's about 50% of drug being given away for free in the U.S. right now because of the -- most of the Medicare Part D dynamic. And in Europe, it's almost equal selling to the U.S. with about, I don't know, 4 countries that they're approved in. So there's so much more to come there. But the best guess right now to 27,000 diagnosed patients, if you just back out the number that are on paying drug, it is a high compliance rate to generate that $2-plus billion of revenue run rate...

So that diagnosis rate had been gone up significantly since the launch of the tafamidis and now it's like about 27%, approaching 30%. But if you actually look at the number of patients on the drug, I don't know if you account for free drug, it's less than 10%. So a couple of questions. Do you think the diagnosis rate, whether it's going to continue to go up, but do you think we would reach the point of a close to 100%? And then once everybody is diagnosed, what's the kind of realistic expectation? What percent of diagnosed patient would be -- would actually end up taken care of?

I don't think it's 10%, I don't think that number works. You may be misquoting that because you don't have the full -- so no one has -- the [ SPs ] that Pfizer works with don't release their data, so you wouldn't have the full number of scripts that are being -- it can't be 10%, just I mean back into that, that would be $550 million or so. It's obviously more than that. But either which way, basically, what you're asking about is number of patients diagnosed versus number of people on drug. And I think the way that it works is, let's put Europe aside for a moment, in the U.S., you'll have about 50% of patients that still get free drug unless there's Medicare Part D reform in one way or the other, which I think could come. To be honest, it's part of a lot of the bills that are being book forth right now is some sort of co-pay relief for coverage on Part D. But if it's still today, a lot of patients getting free drug through foundations. And then you've got a lot of patients that are on pay drug. And I think that the compliance rates are extraordinarily high. It's not like a PCSK9 type of experience right now. Because, again, it's a devastating disease, you're losing the ability to ambulate. And ultimately, you're dying -- you're failing quickly. So you're feeling it, and people have been selling their scripts. Obviously, there is a co-pay relief on the commercial side, which is at least 50% of people who are paying for drug right now as well. Europe, I think you're going to see a very high compliance rate because, again, devastating disease. I mean this is like cancer-style compliance rates because it's a cancer-style devastating disease. Yes, I think that's how I would think about it.

So can you talk about what the kind of IP, intellectual property, position on acoramidis?

Yes. So acoramidis goes out to -- what's the date again, Cameron?

2025 for composition of matter and then, of course, a whole bunch of additional filings for additional formulation and method of use dosing, et cetera, that go up beyond there.

Okay. So the composition of matter patent goes out to 2025. Is that kind of like -- companies use like a crystalline form or is it chemical structure, like a 2-dimensional chemical structure? Is that the original composition of matter patent for 2025?

Yes.

Yes. And I think just getting...

And that includes patent term extension, but yes.

Yes. And getting to your point earlier, I mean, we're already working on a once-daily formulation. So -- actually, it's interesting, if we did once daily anyway, even with just AG10, we get superior stabilization to tafamidis. It's just we wanted to keep everyone at the very highest end of stabilization 24/7. But either which way, we're working on a once-daily formulation. So that would, obviously -- to the extent that we're able to switch patients on that, that would be an extension. And I think for taf, the 2029 date, which is, I think, the most conservative date, that one would apply there. I think you could expect that they're going to be looking to extend the runway there just based on the 80 mg or to 61 mg [ free acid ] formulation or whatever it is.

So when do you think we will see the data about once daily formulation?

Probably 3 years.

2, 3 years. I don't think there's any need to do anything right now, but we're certainly working on it.

So in terms of -- because your coming into the market later, assuming the data is numerically better than tafamidis, what do you think would be a kind of a switching rate from patients on tafamidis to acoramidis? Because obviously, you could catch a lot of new patients. But then by then, a lot of patients are going to be on tafamidis. So switching is important to drive sales faster. So what do you think would be the kind of a switching rate if you have a numerically better drug that you think?

Well, it depends on a couple of things. Number one, most obviously is the delta there. If we're closer to halting the disease and tafamidis continues the progression, I think from a clinician standpoint, one will want to switch as many patients as quickly as possible. Obviously, though, the second key gating factor is how the access to the medicines work. It's already quite onerous to get on to tafamidis. Once you're successfully on tafamidis, the degree to which our patient [ opt ] services and have access of backdrop is really easy to navigate will help dictate the number of switches that we get. But I think if we have a really compelling difference in terms of clinical efficacy and we have something that's at or better than VyndaLink, which is pretty good, honestly, in terms of getting patients on drug, I think you can see significant switching.

Okay. And then you're also running clinical trials for a polyneuropathy trial and polyneuropathy is much, much smaller market than cardiomyopathy. From our experts call a couple of weeks ago, what we've heard was that about 10% to 15% of cardiomyopathy patients have the symptomatic neuropathy. But then they -- he found -- he hasn't found that tafamidis doesn't really work for the symptoms of neuropathy. So I mean, obviously, it's not approved in the U.S. for polyneuropathy. So can you talk about your rationale going for polyneuropathy? And do you think that your main purpose of running the trial is to actually also reduce the neuropathy symptoms in cardiomyopathy patients? Or you're like purely looking into polyneuropathy patients opportunities?

I think the evidence for a full stabilizer being most effective of all the agents in polyneuropathy is even more striking than it is in cardiomyopathy. I mean if you go back just a couple of years, people didn't even really believe -- I mean, there were a set of believers and nonbelievers about whether or not 20 versus 80 would separate. As you probably remember after I just went public, when it first read out and people didn't see that dose separation, people were like, well, I don't know if every more stabilization is going to be better in cardiomyopathy, whereas in polyneuropathy, it's very clearly. Taf 20 wasn't approved in the U.S., as you rightly point out, approved in Europe. Diflunisal, which is a 70% stabilizer does better than taf and actually has a marked clinical effect. Diflunisal, which is a 70% stabilizer, has an equivalent effect as a 70% knockdown agent inotersen. And then Alnylam's 84% partial knockdown has the most effective clinical outcome. So a 95% stabilizer by virtue of all of those data points should be the superior agent in polyneuropathy. And we've got more clinical data to suggest that. Also, it's worth pointing out that the T119M trans-suppressor occurs in the context of the V30M patients which at least early onset tend to be polyneuropathic. So I think, ultimately, there's a great lot of evidence to suggest that a full stabilizer should impact on polyneuropathy symptomatology. And the reason that tafamidis sadly doesn't have an effect for those patients is it's low amount of stabilization. We already bought a good stabilizer, has effect on PN symptomatologies. We know that from Diflunisal. So the reason taf doesn't have it is taf is not a very effective stabilizer.

So in your current trial for cardiomyopathy, are you also looking at kind of a neuropathy symptom improvement?

No, we're not getting a lot of them because, again, wild-type patients don't have it and B-122I patients, by and large, don't have it. We do have some mixed phenotype T60A folks. So maybe there'll be a few neuropathy patients, but no, we won't have a robust data set there.

Okay. And then I want to touch on competitive landscape. So there are TTR silencers and/or stabilizers. So [ course ] is more on the second-generation vutrisiran, Phase III is running. And there, they have a combination with the tafamidis and tafamidis alone. So kind of your view of silencer versus stabilizers. So our expert a couple of weeks ago suggested that when you get to near full stabilization that there's really not much difference between silencer versus stabilizer. And then when you get to that term stabilization, adding silencer wouldn't make a difference. So I want to take your view on those points.

Yes. I think let's start with, again, the molecular pathology of the disease, which is that one is trying to reduce the amount of toxic monomer as effectively as possible. [indiscernible] were falling apart to monomer, and that deposition of that in combi together is what's driving the disease. And I would make the point, as I just made earlier that inotersen and diflunisal delivered about the same in terms of clinical efficacy. So the same amount of stabilization is tantamount to the same amount of knockdown. There's not something superior weirdly happening with knockdown. It's just about limiting that downstream. So if you have a 95% to 100% small molecule stabilizer to meet that similar efficacy, I'd imagine you need a 95% to 100% knockdown agent. And the knockdown agents that I know of best of which are Intellia is 92% or so I think and Alnylam is around 84% or so or in the low 80s. So I would expect, number one, that a small molecule would outperform a partial knockdown agent like Alnylam would have efficacy. Secondly, I think there are 2 design criteria that one is aiming for in this space. One is the precise reduction of toxic monomers. The most precise way to do it is to actually target the disease at its source and eliminate destabilization. It's not a disease of [ TTR ] as you pointed out at the beginning. It's a disease of destabilized TTR. The second key design criteria is to keep the protein around because the protein is doing important stuff, lots of which we don't know about, some of which we do know about. But someone asked me the other day if vutrisiran, if it's a once-quarterly injection is going to be more convenient. But remember, what the patient cares about is how many pills they're taking. You're still taking vitamin A pills every day. And if you forget to, you're driven to night blindness. You've also got 20% or so infusion AEs right now with patisiran, and you're eliminating a key core protein. That's the 12th most important protein in the human body that no one doesn't have and no one has a half dose of and no species doesn't have and no species has a half dose of. So if you can be more precise targeting the disease at its source, deliver better efficacy in a more safe way, that's how I stack up the competitive landscape.

So what do you think of gene editing. You mentioned Intellia so if it ever gets to the market, how do you think of it could actually change how patients as well as the physicians are looking at the disease?

I mean, look, I -- the data is super exciting. Obviously, the data is super exciting. And I think that, that 92% knockdown feels like good to me to get into that like super potent point. I mean there's a whole lot of stuff we still need to figure out in terms of safety of those approaches. And for how long is the agency going to need to see data to get -- and how long are physicians and patients are going to need to see data to really understand that if I could get the same level of efficacy as I can with a small molecule, then I'm going to sit around and do something like that, where you've got chromosomal explosions, you've got potentially untoward integration events, how much do we need to see until we get comfortable with that for the same efficacy as a small molecule, I just -- I personally am not convinced that the equipoise favors that if indeed a small molecule can deliver the same or better efficacy. So it all comes down to efficacy here. I think if we're not able to provide efficacy tantamount to what knockdown agents and gene editing can, I think that's another story. But I don't believe that to be the case based on what my understanding of the disease mechanism is.

So look, let's just say acoramidis data comes out the way you expected, better than tafamidis. When the silencer get on to the market as well, although [indiscernible] pretty far out, so when -- aside from gene editing, when you have those silencers-- the stabilizers, how do you think silencers will be utilized? Do you think it's going to be utilized by the patient or whatnot? Is funding well to your drug? Or it's going to just add it to tafamidis to have a better TTR -- not the sort of stabilization and the toxic protein. So how do you think the market is more repositioning for different drugs on the market beside from gene editing front?

Well, in my view -- because the key piece of data that you left out of that hypothetical is the relative efficacy of us versus the knockdown. But in my view, if we have the same efficacy as the knockdowns do and then they come to market, so they have got a 4x more expensive agent that's less safe with the same efficacy as ours, I believe that one would likely use our drug as a first-line treatment paradigm. And then ultimately, not every drug works for everyone. And so if there are people that progress, for instance, or have very severe disease, perhaps they would use a knockdown, perhaps they would use on top of tafamidis, to your point. And then I think that obviously, even though it's 4x the cost, there are going to be a number of providers that use it because you can buy and bill. And it's a -- and if you're 340B hospital on Medicare, you're buying it at a 32% discount and you're buying and billing it at ASP plus 5 or whatever. So there will be an economic rationale to use a more expensive agent in the U.S. I think that those would be the cases under which it would be used if indeed we all meet at the same efficacy.

So in your view, to summarize, do you think that with acoramidis, like delivering close to -- for TTR stabilization, do you think the efficacy to be at least similar to silencers or potentially could be better?

Yes.

Okay. So what if the silencers come out better efficacy, then, I mean, probably the once a month, once every quarter injection wouldn't really matter to the medical community, correct?

I think if they turn out to be better on efficacy, as I just mentioned, I think this market is going to be efficacy driven. But I do think that at that price point, there'll still be some market share that a small molecule takes, depends on how big the gap is on efficacy. If the gap -- in your hypothetical, which I don't think will manifest, but let's just go with it for a second, that silencers are more efficacious than small molecules, I think silencers would take a majority of the market share, but there would still be cardiologists that are more sort of familiar and comfortable using small molecule agents. And I think that at the price points, that would probably be used ex U.S. quite a bit. But we'd have to see. Basically, it would be a safety rationale, and it comes down to the equipoise in and around the separation in efficacy. Like if it's a small separation in efficacy, but you're eliminating TTR, you've got safety issues. You got the imbalance of CV effects as you saw with patisiran in polyneuropathy, then potentially small molecules take quite a bit of market share. If it's a whomp difference on efficacy, then I think you start to believe that will Alnylam will take a little bit more market share. And if that's true, then I think Intellia would take even more.

Yes. The silencers, I mean, obviously, is expensive. But there is a possibility that once cardiomyopathy indication is approved, they may lower the price, correct? I mean that's a possibility?

Yes, of course. Yes.

Okay. And then for remaining a couple of minutes, I'm going to talk to you about the pipeline. So at the R&D Day, we talked about a certain number of pipelines, but you didn't really talk about infigratinib in achondroplasia. So I just want to ask you on that. So the data -- Phase II data is coming out in the first half of next year. So can you talk about when you presented the data, how many patients are we expecting to see from the Phase II in the first half of next year?

Yes. So basically, just as a reminder, what we're doing is we're interrogating our FGFR inhibitor in 4 different cohorts of patients of about 11 patients each, so a total of 44 patients or so. And what we're looking for is average growth velocities that are hopefully superior to what BioMarin observed with vosoritide. And we're in the third cohort right now of interrogating. At the recent, I guess we didn't get into it was there's not much new to say about versus last year, and we had a lot of programs on the docket. But ultimately, the presentation will be, one, safety, which I think is like the big -- it's the big unknown for FGFR inhibitor is low-dose FGFR inhibition in the pediatric context has never really been tried. So that will be one. And the second will be efficacy, [ AGV ], how does it compare vosoritide ultimately for these patients. I think that if we have at or more efficacy, a daily oral is going to be vastly superior to a daily injection. But it's got to be super safe.

Yes. So basically, you are using -- for infigratinib, you are using, if I remember correctly, [ level 1/3 ] of dosing cancer. It's pretty low. So if you have to guess like a potential side, what kind of [ payees ] would you expect to win on the drug?

Well, what we saw in juvenile tox is long bone growth. So we saw the -- I mean, basically, we saw the opposite of what we're trying to -- we saw an exacerbation of the therapeutic effect, let me put it that way. So that's why we have a cutoff at a certain AGV where we don't want to go above it. We don't want to go above the 90%. I think its 90th percentile of AGV. We don't want to get kids growing too much. So that's the juvi tox that we observed. I mean, I think the -- given the PK profile of the drug, there will be a chance that we hit hyperphos. I mean I would like -- in my best estimate, hyperphos is those lower values. Obviously, it's just a lab value and fully reversible. So I think it would be interesting to dose in fine increments all the way up to where we're seeing MTD effectively in children, which would be -- again, won't hurt them with reversible lab values and then we'll ultimately be able to assess what the maximal efficacy possible is in this disease because I think this should drive quite a bit of efficacy. FGFR3 inhibition should be better than the downstream CMPs that we've been using so far because you're hitting both pathways. You know FGFR inhibition 10 ultimate or -- inhibition of at least 1 of those 2 pathways leads to efficacy. So I don't know why 2 of -- the 2 pathways will lead to less efficacy. It should lead to more efficacy. It's just a question of how much efficacy can you do or wring out of inhibiting that receptor. That's my best guess as to how it plays out.

So you have been running the trial for a while. So would you say that your confidence level for achondroplasia program, would you say it's as optimistic as it before, better compared before you started the trial?

Well, it's way better, but then before I started the trial because I had no clue what FGFR inhibition would do, we had juvi tox, Juvi tox in an animal model. But it's not like in the ATTR case where you're going in with a precedent mechanisms of the same patient population, and so you have a better idea of what the safety profile looks like. You never freaking know what's going to happen when you move into a new population. Thankfully, for the kiddos that we're trying to serve here through the first 2 cohorts, we are kind of benign safety profile. So I feel better about it, for sure.

Okay. So our time up. But Neil, could you actually talk about a couple of key catalysts that we haven't talked about that you are excited about in at least the first half of next year or next year?

Yes, yes. First and foremost, I think about that, the wave of 4 important programs. And I think within that, we discussed achon and ATTR, but the one we didn't discuss is ADH1 where we had 100% responder rate now across 2 parts of the clinical trial. I think the key catalyst there is going to be the meeting with the FDA and the kickoff of the Phase III. Because I think that for that trial, you've got to revise up your POTS to a pretty high degree. We're the only player in town and with 100% response rates, I think we've got a really interesting drug to serve patients there. So that would be one catalyst to be looking for. The second catalyst to look for, I think, would be a proof of concept in our dystrophic epidermolysis bullosa trial. I think you and I discussed a fairly risky approach with a huge protein that you're putting back into people's body. But I love the Phase I/II data where we showed dose-dependent increases in C7. So we'll see if that correlates into something that's meaningful for patients. That Phase II POC should read out sometime in January. And then I think the final one, I don't know if we'll hit it in the first half or second half is our LGMD2i trial, where we've basically got a elegant substrate replacement therapy approach. And within that, we'll see whether or not we can actually elevate the amount of constellation of that alpha-dystroglycan complex, which I think could be and lead to an accelerated approval if you look at what happened in DMD. That's 7,000 to 10,000 patients. It's a big unmet need. So those are 3 things that are on my mind in addition to obviously the ATTR and achon. I don't know, Cameron, if you add one?

A lot more. We got the PH1 as well. We've got SHP2 data, got a development candidate for KRAS. I think all of those things should be material as well.

Okay. So since our time is up, thank you very much. And Neil and Cameron, thank you for your time and the discussion today, and best of luck on the data coming out.

Appreciate it. Yes, yes, we're excited. Thanks.

Thank you.