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Thanks, Yvonne. Thanks, everyone, for joining us today. So I'm joined by Bridgeline Management, Nir Kumar, Founder and CEO and Cameron Tuggle, Chief Strategy Officer at BridgeBio. So thanks for joining us today. And as you know, the topic of today is one of the upcoming Phase III data for echoramidis and KTR amyloidosis cardiomyopathy.
So, Neil and Cameron, maybe we can start with 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. Duffy to kick it off and thanks again, Yoon, 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 multi $1,000,000,000 franchise that can help a lot of patients like agoramidis and with several Phase 2, Phase 3 is delivering right behind it. Hopefully, we can build a type of company that's rarely built in the rare disease community. So just in terms of acoramidis, obviously, this is a nested trial sign 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 CBH and mortality. Trial was designed almost exactly the same as ATTRACT, which most people will be familiar with, was Pfizer's trial where they were interrogating FAMDS' effect on AT RCM 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 that are over enrolled in the trial to ultimately get to the point where if we deliver 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 you could actually go over to next year?
Do I think there's a chance what? Sorry.
Go over to next year or to next year?
No, probably not. I mean, it's timelines are pretty well set right now. We had last patient, last visit already. So we're in the game just in terms of database close, 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 number one priority here. So we're working with Duke, working with our vendors. But I think that I think you should expect data at the very end of this year would be my best guess right now.
So this is over 6 30 patient trial, pretty large. And then you said last patient exited already. So how long does it take to actually lock the database, clean it and then analyze the data?
Couple of months. I mean, typically that's what we found is it takes 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 3rd parties, but usually it's about 2 months.
So towards the end of the year, it's a holiday season. So do you think that you could provide more narrower 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 timeline. But right now, that would be inappropriate, I'd
say. Okay. So Part A data coming out towards the very end of this year. So this is a 6,000,000 walk distance at 12 months time point. So before we're getting into data expectations, I want to ask you about patient profile that we can compare to the family SERP Phase III trial.
So in the family SERP Phase III, about 60% of our patients were categorized as heart association class II and about 30% was a class of 3. And then when you look at the wild type versus variant, it was a 75% versus about 25%. So based on that information, do you think your patient profile in the trial would be similar?
Yes. So basically, I think that, again, the trial design, inclusion and exclusion criteria, everything was basically designed to match up. We've got Class 1, 2, 3 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 UK, 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, 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, 3 55 meters or so in that range.
So pretty similar. I mean, it was designed to be similar.
Okay. And then obviously, destabilized 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 when we see like in vitro data, like last week at the end of the day, you guys showed the in vitro data looking at the targeted TTR binding site occupancy. And then you got your product that shows close to 100%, whereas the Tafamidis at 80 milligrams showed about 50% to 60%.
So that's a in vitro data. But have you also looked at TTR serum levels in terms of normalization comparing the Choromyris versus the Pharmacy 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 aciramidis versus what's a little less than 50% stabilization at 80 mgtafamidis. But those are obviously in vitro or we might consider in vitro assays even though you're taking patient Sarah in many cases. We've also looked at as you saw from our Phase 2 data serum TTR levels, which obviously should elevate as you stabilize and what we saw was about 50% increase serum TTR levels as compared to what Tafamidis is able to generate a high dose. And so any measure you want more 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 Kd2s, you're binding more target and ultimately doing a better job of gluing the tetramer together, driving that hydrogen bonding at the bottom of the thyroxine binding pocket with a slightly more enthalpic binding mode as we published in J. MedChem. I think all those dots fit together pretty nicely.
And at the same time Pfizer has indicated that they are, seeing 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 the NEGM paper, NEGM 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 FBE 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 RCmax. 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 levels are elevated in our with our drug versus their drug, again, in a cross draw comparison, and I'm not sure that one 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 2080 in terms of stabilization because of the excess albumin binding that they have, 4 times dose increase only at least to about 2.5 times exposure and a small amount of increased stabilization. Now why on earth would diflunasol handily outperform TAF-twenty in polyneuropathy. So they're not 100% stabilizing anything.
Okay. So on distance at 12 months time point, then you set the baseline of a patient's about 3 50 meters similar to the families. So obviously then, we could expect the placebo decline of 60 meters in your trial compared to similar to what Tafamidis says Tafamidis trial has shown. So one question, there are a couple of questions. One is that in Pfizer's trial, about 30% about 1 third of the patients were on 20 milligram dose, which is not optimal.
And then they showed 25 milligram decline at 12 months, whereas placebo showed about 60. So do you think that had they had all patients on 80 milligram, not 1 third on 20, do you think their 6,000,000 walk distance decline would be I don't know, this is kind of a simplistic way, but about a third less than 25 meters? No.
Or at
least less than 25 meters?
That's not how math works.
But at least less than 25 minutes.
Yes. No, I think you could 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, age 10 agoramidis shows near complete TTR civilization, I mean, isn't it reasonable to expect that it's going it could have hurt, but not just slowing the decline, but could potentially stop the progression. So that instead of expecting, hey, certain levels certain years of decline at 12 months at time point, can we actually expect that whatever it shows, whether it's a decline or stabilization, it would be similar to healthy elderly population?
Well, you got to remember ATTR Centimeters. So yes, I think it could. And I think it will in some patients, whether or not a very sick patient with ATTR Centimeters isn't it can evolve the disease at that point. One doesn't know because these are sicker patients and then 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 could catch it earlier and you may be doing 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 the differentiation, especially if it connects up with, again 2 times the stabilization, 50% more of serum TTR elevation, outperformance on key biomarkers like BNP as we saw in our Phase II, I think all of those things will go hand in hand.
So when we see Part A data, we are going to see those cardiac biomarker data as well?
We may. I mean, okay, we're not.
I think the cardiac biomarkers are more likely to come in an academic presentation next year.
Oh, There you go. Academic presentation.
Okay. The clinicaltrials dot gov website and cardiac biomarkers or I mean, I'm sure that you're measuring periodically, but a 30 month time point and not necessarily a 12 month time point. So in terms of so when the data comes out, STREET is going to compare your data to the pharmacist data. And obviously, this is a cross study comparison. So as you pointed out, if you show 6,000,000 warrants decline in teens versus the families that had shown 25 milliliters.
But it's a given that it's a cross study comparison, obviously, we are looking for numerical difference. But how much numerical difference really has to be there in order for the financial community to feel more comfortable that, hey, AG10 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 patient community to feel that there's a difference. And I think that's on a couple of different dimensions. Number 1 is, I think that's why we said 20% or more relative risk reduction, which puts you into teens, 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 did 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 and morbidity benefits? I mean, is there a kind of like a correlation between 6,000,000 walker distance decline versus the cardiovascular outcome?
Yes. There is the Lane paper lays all of that out. There's actually a couple of different papers, but the best is the Lane et al 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 is a good predictive element with serum TQR levels as well.
So yes, I think both of those will be interesting to look at the end.
But is there like a I mean, it's really speculative, but is there a certain level of the 6,000,000 walker distance that 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 will be better than the pharma is?
Yes. I think if you're talking about something like 8 to 10 meters in terms of 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 into teens, obviously, but in the high teens, I think that would ultimately, if you looked 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 80%, 37% to a little under 50%. You had a 20% relative risk reduction between the 20 80 mix 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're able to drop a 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 who want to dance with their grandkids or want to get your mail or whatever. So you'd say these are typically healthy people until they get ATTR Centimeters. 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 with the EGRAMIDUS, assuming that the placebo declines similarly as the Tafamidis Phase III trial, which is about 60 mirrors, you would expect with the parameters that 12 months around 15, 17 meter decline? Is that
Yes, I think in the teens is appropriate. Yes, I think 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.
Okay. And then in terms of a trial, like a patient profile similar except for the fact that you may have a little more wild type patient. Yes,
which is natural given the evolution of how we're diagnosing the disease and also the countries where we ran trial
When you look at your earlier data, the parameters is pretty important against the variant. So do you think having more a little bit more agitated patient might have some impact on the outcome or is too negligible?
We didn't see significant difference in that in Attract between the mutant and the wild type populations and wequipotent. 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?
I think that actually looks similarly I know that people generally think that hereditary form is sicker, but that's not the case as far as we can tell and attract. I don't know. What were you saying, Kevin?
I was just going to say that the treatment effect size on both mortality and 6 minute walk was almost identical and attract 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 atoramidis and for variant patients than those with wild type. And that's because they start with a less stable form of TTR and you 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 Attract and so we don't have that expectation going in.
Okay. So the one big difference that I see between your trial and Pfizer trial is really number of patients. If I calculate correctly, I mean, my math is correct. You have like over 40% greater number of patients in your trial. So that's very overpowered.
So with that kind of a powering assumption, I mean, it's highly unlikely that studies are going to miss the endpoint because, you know, placebo performed a little bit better than whatever. But given that you have 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 the pharma this or you don't think that's going to impact much at all? You know what I'm saying?
I mean the standard error given that Not a soul. Is in the denominator, it will be tighter. If you're sampling the same distribution, but with more n, then yes, I guess, standard error would be tighter.
Well, do that so question is the data points are tighter. So in a way that when you present the data in aggregate in average, could we actually show better outcome?
No, because I mean standard errors will 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 to 15. It's going to be 18 with a little bit more confidence, which is exactly why you just said the child is powered better too. That's all you would see, but you would still see the same number. Do you see the number that delivers?
I mean, if tafamidis ran twice the number of patients, the theory of the case would be that they'd still hit the same means, just different standard error, right?
So what was your reason behind like the increasing the number of patients by 40% compared to
Well, we started with a target of 510 because it was COVID and we were afraid that we would have a higher sites and it felt pretty unethical just to say, hey, look, 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 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 if Part A is successful, you'll file for approval in the U. S. And Europe, but needed 2022, and they could lead to full approval. So question to you is that the pharmacist was approved based on the current lab cut, so the morbidity mortality.
And then from your discussions with the regulators, they are allowing you to file based on the 6,000,000 walker distance. So can you elaborate on the discussions and why do you think regulators will allow you to file on 6,000,000 work distance whereas they approved the families on clinical outcomes?
Well, the regulatory agencies have always been clear about what constitutes an approvable full endpoint, 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 endpoint. In this case, the agency actually worked with us to identify 6 minute walk as a trialable endpoint, not unlike they must have with Alnylam because Alnylam is obviously running a trial that only has 6 minute walk as an endpoint and they expect full approval of that. We're obviously moving on to ulcerative mortality data. But yes, I mean, I think we basically had that conversation with the cardiorenal division. And we've had that conversation in the Europe and we're pretty confident that we'll be able to file on that.
It's not like a biomarker like oxalate reduction or something. And in one of our trials, it's a true functional endpoint.
Okay. So what happens so, okay. So is there any kind of like a 16 year walker distance data you would need to show? Or does a p value of less than 0.01?
Yes, p value of less than
sufficient enough for
1, yes.
Okay. All right. So do you expect a standard review from a review of the FDA once you file for approval?
Yes. And we expect Once you file for approval? Yes. And we expect that we would use our PRV as well.
Okay. All right. So by the time Zohr gets approved, you would have a Part B data, which is expected
to be Yes.
I mean, we
really hustle it out. It would be early 2023 where we launch and we get the Part B data just shortly after that, few months after.
Okay. So in Part B, so 12 months patients are on the calamities versus placebo, but after 12 months, physicians can actually utilize the pharma Yes. Right, up to 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 UK and in broad spots 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 for months.
And most of those patients aren't on tafamidis, because either in the U. S, they access our trial because they couldn't afford 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 present will be. Certainly, we designed the trial such that tafamidis to defective tafamidis on mortality and CDH would be minimal because you don't see a Kilometers curve separate up until 15 months or so as a minimal separation at 18 months. And so that so yes, but I can't comment on the percent.
Okay. So when physicians are allowed to utilize the Tafamidis, can they actually add Tafamidis on top of Iperamidis or is it only for placebo patients?
No, this is a blinded trial. Yes, they can add it on top.
All right. But do you think that additional will make a difference?
No. Because we've shown biochemically that aporamidis displaces tafamidis. And so I don't it's not like it's 2 separate binding sites and there would be some additive effect there. I don't think you would expect to see anything added.
Okay. So in Pfizer's Phase III trial, Tafamidis on Tafamidis, the 30 month mortality rate was close to 30%. I think the placebo was about over 40%, about 43%. So when we look at the risk reduction, it shows about 30%. So what do you think you would need to show in order to for medical community patient or Wall Street to actually look at it, hey, numerically, the Coramadis is better in terms of controlling hospitalization, deaths and things like that?
Mean, I think in that 25% range, 15% relative risk reduction, if we read 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, connecting the dots to a better serum TTR in a superior stabilization, that would be a resounding victory.
Okay. So we're not getting into commercial strategy. So obviously, you guys have been developing the product, noting that it's a better drug than the family. So when the data comes out, if it's numerically clearly better and there is no question, But what if it's kind of like a similar, let's just say 6,000,000 walk a distance, it's better, but then somehow on the mortality, morbidity benefits, it wasn't really that much different. How do they 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 elements of the strategy. I'd say 1st 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, etcetera, to be a 1 of 2, since we're coming later to the market, probably change elements of the way that we do distribution. And then also it would if we continue to believe that we were superior like in the case where you just said 6 minute walk played out, but somehow it didn't play out in mortality.
I think it would completely change Phase 4 strategy, where right now we're very focused on primary prevention and trying to understand how to move this therapy as early as possible since 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.
Yes, 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 there?
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 offer to a company an interesting place to build. And I think we could build there not only for this franchise, but others of our franchises. So that I would expect that we could do something maybe early with a 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 on to the market, what kind of the uptake is there that 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 you? So the accomodist is first daily, you always say the pharmacy wants daily. Does that kind of play in to pricing strategy?
How so?
Well, obviously, once a daily is a lot more convenient than
Well, first of all, these are 72 year old pretty sick patients 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 the final assessment on the market over 2 years and have you heard what the kind of a 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 4 countries that they're approved in. So, 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 $2,000,000,000 plus the revenue
run rate. So Davenos rate has been going up significantly since the launch of the family. So 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 it accounts for free drug, but it's less than 10%. So a couple of questions.
Do you think that the drug I'm not guessing it's going to continue to go up, but do you think that he would reach the diagnosed, what's the kind of realistic expectation, the what percent of the diagnosed patients would actually end up taking
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 can't be 10%. Just I mean back into that, that'd be $550,000,000 or so it's obviously slightly 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 put forth right now is some sort of copay relief for coverage on Part D for the elderly. But if it's But if it's still today, you've got a lot of patients getting free drug through foundations and then you've got a lot of patients that are on paid 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 done fairly quickly. So you're feeling it and people have been filling their scripts. Obviously, there's copay relief on the commercial side, which is at least 50% of people who are paying for drug right now as well.
In 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, agoramidis goes out to what's the date again, Cameron? 2,035
for composition of matter and that's and then of course a whole bunch of additional filings for additional formulation and method of use dosing etcetera that go beyond that.
Okay. So the composition of Melopetin goes up to 2,035, is that kind of like a do companies use like a crystalline form or is it a chemical
like a
2 dimensional chemical structure? Is that the original composition of a matter of fact, 2,045?
Yes. And I think just getting to
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 20 fourseven. 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 the 61 mg free salt formulation or whatever it is, the megalomene thing.
So when do you think we're able to see the data about what's daily formulation?
Probably 3 years 2 or 3 years, yes. I don't think there's any need to do anything right now, but we're certainly working on it.
So in terms of so because you are coming into the market later, assuming that the data is numerically better than the pharma list, what do you think would be the kind of switching rate from patients on Tafamidis tacrolimidus? Because obviously you could capture a lot of capture a lot of new patients, but then by then a lot more 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 switching rate if you have a numerically better drug than you think we should?
Well, it depends on a couple of things. Number 1, most obviously is the delta there. If we're closer to halting the disease and Janus 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 hub services and our access 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 Vindalink, which is pretty good, honestly, in terms of getting patients on drug, I think you could see significant switching.
Okay. And then you're also running clinical trial for pulneuropathy trial. And pulneuropathy 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 has found that the phthalates doesn't really work for the symptoms of neuropathy.
So I mean, obviously, it's not approved in the U. S. For neuropathy. So can you talk about your rationale going forward in neuropathy? And do you think that your main purpose of running the trial is to actually also reduce the neuropathy symptoms in haleiomyopathy patients or you're like surely looking into polyneuropathy patients opportunity there?
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 non believers about whether or not 20 versus 80 would separate. As you probably remember after I just went public, when a track first read out and people didn't see that dose separation, people were like, well, I don't know, every more stabilization is going to be better in cardiomyopathy, whereas in polyneuropathy, it's very clearly the case. TAF-twenty wasn't approved in the U. S, as you rightly point out, approved in Europe.
Diflunasol, which is a 70% stabilizer, does better than TAF and actually has a marked clinical effect. Diflunasol, which is a 70% stabilizer, has an equivalent effect as a 70% knockdown agent 9 atersen 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 transallelic transuppressor 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 to suggest that a full stabilizer should impact on polyneuropathy symptomatology.
And the reason that tafamidis likely doesn't have an effect for those patients is it's low amount of stabilization. We already want a good stabilizer has effect on PN symptomatology. We know that from daflunisal. So the reason TAF doesn't have it is TAF is not a very effective stabilizer.
So in your current Phase III 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 V122Y patients by and large don't have it. We do have some mixed phenotype T68 folks. So maybe there'll be a few neuropathy patients, but now we won't have a robust data set there.
Okay. And then I want to touch on competitive landscape. So there are silencers, TTR silencers and or stabilizers. So post season more on the 2nd generation vitrusiran 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 export a couple of weeks ago suggested that when you get to near full stabilization, there is really not much difference between silencer versus stabilizer. And then when you get to that full 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, tetramer falling apart to monomer and that deposition of that, it clumping together is what's driving the disease. And I would make the point as I just made earlier that inotersen and defenisol 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 or 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 about 92% or so, I think and Alnylam is around 84% or so or in the low 80s. So I would expect number 1 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, most precise way to do it is actually target the disease at its source and eliminate destabilization.
It's not a disease of excess CTR as you pointed out at the beginning, it's a disease of destabilized CTR. 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 vitrusiran, if it's a once quarterly injection is going to be more convenient. But remember, what a 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 abundant 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, target the disease at its source, deliver better in a more safe way, that's how I stack up the competitive landscape.
So what do you think about generic you mentioned the intelligence. So if we ever get to the market, how do you think that could actually change how patients as well as physicians are looking at the disease?
Yes, I mean, look, I thought the data is super exciting. 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 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 on toward 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, I'm 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 let's just say Acrometis data comes out the way you expected, better than Tafamidis and then silencers get on to the market as well, although vitrocirone is pretty far out. So when aside from generative, when you have those silencers and the stabilizers, how do you think silencers would be utilized? Do you think it's going to be utilized, the patients who are not responding well to your drug? Or it's going to just add it to Tafamidis to have a better TTR, not this sort of stabilization and given below the toxic protein. So how do you think its market is going to be positioning for different drugs on the market aside from genetic import?
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 4 times 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 4 times the cost, they're going to be a number of providers that use it because you can buy and bill it and it's a 3.4 and if you're 340B hospital on Medicare, you're buying it at 33% discount and you're buying and billing it at ASP plus 5 or whatever.
So there'll 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 the coronavirus like delivering close to TTR sterilization, do you think that efficacy would be at least similar to RNA silencers or potentially could it be better?
Yes.
Okay. So what if the silencers come out better efficacy? Then, I mean, probably at the point 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, they'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 that there would still be cardiologists that are more sort of familiar and comfortable using small molecule agents. And I think that at a price point, so it would probably be used ex U.
S. Quite a bit, but we'd have to see. Yes. I mean, 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 and polyneuropathy, then potentially small molecules take quite a bit of market share. If it's a lump on difference in efficacy, then I think you start to believe that Alnylam will take quite a bit more market share. And if that's true, then I think Adsellio would take even more.
Yes. The silencers, I mean, obviously, it's expensive, but there is a possibility that once cardiomyopathy indication is approved, they may go on the device, correct? I mean, that's a part of the problem. Yes.
Of course. Yes.
Okay. And then for remaining couple of minutes, I'm going to talk to you about the pipeline. So at the R and D day, we talked about certain number of pipelines, but you didn't really talk about infillibratinib and kind of lazy. So just want to ask you on that. So the data Phase 2 data is coming out in first half of next year.
So can you talk about when you present the data, how many patients or what we are expected to see from the Phase 2 infrasarctomy 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 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 suicide. And we're in the 3rd cohort right now of interrogating it. The reason I guess we didn't get into it was there's not much new to say about it versus last year and we had a lot of programs on the docket.
But ultimately, the presentation will be 1 safety, which I think is like the big unknown for our FGFR inhibitors is low dose FGFR inhibition in the pediatric context has never really been tried. So that will be 1 in the second will be efficacy AGV, cause a comparative 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 infagretinib, you are using, if I remember correctly, 1 30th of a dose in cancer. It's pretty low. So if you have to guess about like a potential study, but what kind of payers would you expect to weigh for a drug?
Well, what we saw in juvenile talks is a 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, 90th percentile AGV.
We don't want to get kids growing too much. So that's the juvitox that we observed. I mean, I think the given the PK profile of the drug, there will be a chance that we hit hyperphosph. I mean, I would let what in my best estimate, hyperphosphat 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, we're hurting 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 can ultimate or inhibition of at least one of those two pathways leads to efficacy. So I don't know why 2 of the two pathways would lead to less efficacy. It should lead to more efficacy. It's just a question of how much efficacy can you juice or ring out of inhibiting that receptor.
That would be my that's my best guess is how it plays out.
So you haven't been running the trial for a while. So would you say that your confidence levels for your chondroplasia program, would you say to as optimistic as it before better compared to before you started the trial?
Well, it's way better than before I started the trial because I had no clue what FGFR inhibition would do. We had JUVITOX, JUVITOX into the animal model, but it's not like in the ETTR case where you're going in with the 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 happen when you move into a new population. Thankfully, for the kiddos that we're trying to serve here through the first two cohorts, we're kind of benign safety profile.
So I feel better about it for sure.
Okay. So our time is up, but Neil, could you 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?
Well, I think Yes. Yes, yes. 1st and foremost, I think about that the wave of 4 important programs and I think within that we discussed ACON 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 3, because I think that for that trial, you 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 proof of concept in our dystrophic epidermolysis, Bellosia trial. I think you and I discussed fairly risky approach with a huge protein that you're putting back into people's body, but I love the Phase onetwo 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 2 POC should read out sometime in January.
And then I think the final one, I don't know if we'll hit it in first half or second half is our LGMD2I trial, where we've basically got a subs elegant substrate replacement therapy approach. And within that, we'll and lead to an accelerated approval if you look at what happened in DMD, that's 7000 to 10000 patients, that's big unmet need. So those are three things that are on my mind in addition to obviously the ATTR and AECON. I don't know Cameron, if you add one.
A lot more. We got the PH1 as well. We got SHIP-two data. We 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 discussion today. And best of luck on the Phase III data coming out at the end of the year.
Thank you. Appreciate it. Yes, yes, we're excited. Thanks.