Good day, and thank you for standing by. Welcome to today's discussion with BridgeBio, which will cover the company's ATTRibute-CM phase III results as presented at ESC. Currently, all participants are on a listen-only mode. Please be advised that today's conference is being recorded. I would now like to introduce you to the speakers for today.
Julian Gillmore, MD, PhD, Professor at University College London, and Head of University College London Center for Amyloidosis, and National Amyloidosis Center Research Lead. Jonathan Fox, MD, PhD, Chief Medical Officer of BridgeBio Cardiorenal. I will now hand the call over to Neil Kumar, PhD, CEO of BridgeBio. Please go ahead.
Thank you, Operator, and thanks to everyone for joining. The team is assembled here in Amsterdam, where we had the privilege of sharing further details from our ATTRibute-CM phase III clinical trial results of acoramidis in ATTR cardiomyopathy. I use the word privilege on multiple levels. Number one, that with these data, we have the opportunity, as we previously discussed, and the responsibility to serve patients as broadly as possible with this drug. Two, that the data reported and the clinical science story that will continue to build are only possible with the tireless work of the physicians that participated in this trial. I had the opportunity to meet many of our esteemed physician partners this week and was energized by their passion to help patients with this medicine.
No one exemplifies that more than Dr. Julian Gillmore, who we have the good fortune of having on our call today to review the data in some detail, and who has played an incredibly important role in the development of ours and other important therapies in this space. Moving to the presentation now, I'll be calling out slide numbers as I progress, and on slide three, you can see the structure of the discussion today.
I will briefly motivate the discussion with a reminder of the molecular hypothesis that underpins acoramidis and its development. I'll then turn it over to Dr. Gillmore to speak more about the phase III clinical data, and then I'll return briefly to contextualize that data and provide next steps for the organization. Moving to slide four, a brief reminder of the design principles that motivate our best-in-class stabilizer hypothesis.
The first and most important design principle is to maximize stabilization, therefore minimizing the production of toxic monomer. At least three strains of evidence suggest to us that in doing so, we can optimally impact patient health. Firstly, the well-established genotype phenotype of the disease in the context of the variant population, shows us that variants associated with greater levels of tetramer destabilization present a more pathogenic form than do less destabilizing variants.
Furthermore, the existence of two prominent transthyretin suppressor mutations highlights that ever greater degrees of destabilization in the context of a pathogenic mutation are correlated with better outcomes for patients. The so-called T119M rescue mutation is the most potent of these restabilizers, and its often full rescue of the disease provided the blueprint for our own drug program.
The second strand of evidence suggesting that ever better stabilization improves clinical outcomes is the ATTR-ACT trial, run to understand the impact of tafamidis in the ATTR-CM population. In that trial, the 80 mg dose of the drug, which is about a 50% stabilizer, as detailed in Pfizer's regulatory submissions, outperformed the 20 mg dose, which is approximately a 35% stabilizer. The final strand of evidence comes from ATTR polyneuropathy studies, where again, ever greater stabilization or toxic monomer reduction via knockdown provided ever better benefits to patients.
Understanding the dangers of cross-trial comparisons, we nevertheless observed that tafamidis 20 mg was outperformed clinically by high-dose diflunisal, which achieves close to 70% stabilization. Furthermore, the diflunisal results are close behind the patisiran, which is a 70% mean max knockdown agent, suggesting that similar quantitative levels of knockdown and stabilization lead to similar outcomes.
Again, consistent with the biochemical model of the disease, driven by TTR dissociation and toxic monomer reduction. Finally, patisiran, with a 4% mean max knockdown, seems to outperform the 70% stabilizer and knockdown agents. The second design principle is to preserve the native transthyretin tetramer. TTR is highly evolutionarily conserved, with no known species, including humans, being haploinsufficient or null for the protein.
Further, the protein is maintained at high concentration, being one of the most... 20 most abundant protein in the sera, and its relatively short turnover time suggests a high energetic cost for keeping it around. It plays known roles in vitamin transport to the eye. Moving to slide five, I'll briefly review the tenets of superior stabilization that were built into acoramidis. First, the drug sees more target, owing to a much lower degree of albumin binding than has tafamidis.
Second, the drug demonstrates superior binding to the target, employing a smaller KD2. And finally, the drug does a better job of gluing the targets together upon binding, employing an exalted binding mode and inducing hydrogen bonding at the bottom of the thyroxine binding pocket to super stabilize the tetramer. This action essentially phenocopies the aforementioned T119M rescue mutation. All right, let's move to slide six, as we've reviewed with all of you in the past, the in vitro and in vivo signatures of superior stabilization have been documented and published on. I won't go through these details today in these data today in any detail, but I'll provide them for reference or questions later if there are any. All right, let's move to slide seven, where we see new data here that were presented at this week's ESC meeting.
On the y-axis of the presented chart is the percent stabilization as measured in our Western blot assay, and on the x-axis are listed common variants associated with ATTR. Two points stand out from these data to me. Number one, that acoramidis is able to stabilize consistently across the variant spectrum, and that two, acoramidis stabilization reliably outperforms that of tafamidis at clinically relevant concentrations. Moving to Slide eight, we re-present the data that was shared a few weeks ago, showing in a post-hoc exploratory analysis that took advantage of the fact that tafamidis was allowed for drop-in in our trial, that we were able to measure the mean change from baseline of serum TTR, a good in vivo reflection of stabilization.
On the chart, we can see here that acoramidis outperforms tafamidis in this same trial, and that consistent with biochemical studies, no further outperformance is observed from the combination of agents, consistent with studies showing that acoramidis displaces tafamidis at clinically relevant concentrations. Okay, with that as a backdrop, I'd like to turn it over to Dr. Julian Gillmore to present the detailed phase III data.
Thank you, Neil. It's a great pleasure to present to you the results of the ATTRibute-CM trial of acoramidis in transthyretin amyloid cardiomyopathy. Next slide, please. So ATTRibute-CM was a randomized, double-blind, placebo-controlled trial of 30 months fixed treatment duration. Here you see the schematic of the overall study design. Key eligibility criteria shown on the left. Eligible patients had a diagnosis of ATTR amyloid cardiomyopathy established either on biopsy or non-invasively and NYHA Class 1 to 3 heart failure. 632 patients were randomized 2:1 to acoramidis or matching placebo. Use of open-label tafamidis was permitted after 12 months, if locally available, and at the discretion of the investigator. The 30-month primary endpoint was a hierarchical analysis using the Finkelstein-Schoenfeld method of all-cause mortality, frequency of cardiovascular hospitalizations, change from baseline in NT-proBNP, and change from baseline in 6-minute walk distance.
At the end of the 30-month blind in-intervention period, all eligible participants were invited into an open-label long-term extension. Next slide. The study arms were well-balanced at baseline in terms of patient demographics and disease characteristics. Mean age was 77, and most participants were male. Just under 10% were TTR variant carriers. Median NT-proBNP and mean eGFR were characteristic of this patient population. Randomization was also stratified according to these characteristics, which are widely used in clinical practice to stage the disease. As expected, mean serum TTR was at the lower end of the reference range. And as I mentioned earlier, concomitant tafamidis use was permitted after 12 months and was considerably more prevalent in the placebo arm. Next slide. The study met its primary endpoint with a highly statistically significant P value of less than 0.0001.
Importantly, 58% of the win ratio ties in the primary hierarchical analysis were broken by the first two components of the primary endpoint: all-cause mortality and cardiovascular hospitalizations. An analysis using these two components of the primary endpoint alone was statistically significant in its own right. The results were consistent across subgroups, with the point estimates favoring acoramidis over placebo and confidence intervals to the right of unity, with few exceptions. Next slide. Turning our attention to the components of the primary endpoint, here you see the Kaplan-Meier curve of cumulative all-cause mortality. The treatment effect favored acoramidis over placebo, with an overall survival of 81% on acoramidis at 30 months, which represents an absolute risk reduction of 6.4% and a relative risk reduction of 25%. Next slide, please. 78% of the deaths were cardiovascular in nature.
Again, the treatment effect favored acoramidis over placebo with respect to cardiovascular-related mortality, representing an absolute risk reduction of 6.4% and a relative risk reduction of 30%. Next slide. Acoramidis treatment was associated with a 50% reduction in cardiovascular hospitalizations. That was, in itself, highly statistically significant, with a P value of less than 0.0001. Again, the results were consistent across subgroups, with the point estimates consistently favoring acoramidis over placebo and confidence intervals to the left of unity, with few exceptions. Next slide. Moving on, we see that acoramidis treatment was associated with a blunting of the progressive rise in NT-proBNP, which is characteristic of this patient population and has been shown to be of clear prognostic value in this disease. The results were highly statistically significant at 30 months.
Similarly, the treatment effect with respect to effort tolerance, as assessed by six-minute walk distance, favored acoramidis, and this was also highly statistically significant and clinically meaningful, resulting in a 40 m difference at 30 months. Next slide. Relative preservation of quality of life was evident among patients on acoramidis from the beginning of the 30-month observation period, mirroring the early separation in NT-proBNP that you saw in the last slide. Difference at 30 months was highly statistically significant. Consistent with the molecular mechanism of the drug and preclinical data demonstrating near complete stabilization of therapeutic drug concentrations, serum TTR and an in vivo reflection of increased stabilization, was promptly and persistently elevated throughout the trial. These data are consistent with previously reported data from phase I and II trials in healthy volunteers and patients with ATTR amyloid cardiomyopathy respect. Next slide, please.
Among patients who reached 30 months, a higher proportion on acoramidis treatment experienced either a reduction in NT-proBNP or an increase in six-minute walk distance from baseline to 30 months. Nearly half of the acoramidis cohort experienced a reduction from baseline in NT-proBNP, and 40% of patients actually walked further at 30 months than they did at baseline. Taken together, these data indicate benefits across the board with acoramidis and the tantalizing possibility of genuine clinical improvements on the drug. Here you see a high-level safety summary of the data. Overall, acoramidis was generally well tolerated, with no findings of potential clinical concern. The incidence of treatment-emergent adverse events was balanced between the arms and favored acoramidis with respect to treatment-emergent serious adverse events. Next slide. In conclusion, the results of the ATTRibute-CM trial are robustly positive.
The study met its primary endpoint with a highly statistically significant P value of less than 0.0001, and a consistently positive treatment effect across all components of the primary endpoint and across patient subgroups. Importantly, 58% of the win ratio ties in the primary analysis were broken by the first two components of the primary endpoint, all-cause mortality and cardiovascular hospitalizations, and an analysis was significant in its own right. Remarkably, 30-month survival and cardiovascular hospitalization rates among patients on acoramidis approached those in an age-matched population without ATTR-like cardiomyopathy. The emerging safety profile of acoramidis remains reassuring, with no safety signals of potential clinical concern identified in the study. Next slide. I'll hand back to you.
Thank you, Julian, again, for your leadership and dedication to patients in this program. I'd like to wrap by addressing questions we've been receiving from the physician and investor community alike. How might we understand these data in the context of past trial data and in the context of today's patient population? Obviously, there's been no double-blind, head-to-head trial performed, so cross-trial observations must be taken with that strong caveat in mind. Although I honestly think we should run a double-blind head-to-head in the future. On slide 23, we remind everyone of the salient outcomes that we believe are consistent with the molecular best-in-class hypothesis I began today's call with. Simply, we find ATTR-CM patients surviving more and going to the hospital less than had ever previously been observed in clinical studies, to our knowledge.
This owes to levels of risk reduction and actual patient improvement that also have not been previously observed, to our knowledge, and it reinforces the tie I discussed between ever better levels of stabilization and ever better clinical outcomes. Moving to slide 24, we observe that the 30-month survival on acoramidis in this trial is 81%, remarkably close, as Dr. Gillmore suggested, to the 85% actuarial life expectation, absent ATTR cardiomyopathy for our clinical trial population. This suggests a dramatic reduction in ATTR cardiomyopathy death, death risk. Furthermore, we observe this observation with a near normalizing of hospital frequency, a key measure of morbidity in this population. The absolute values of survival and hospitalization are both superior to what has been observed in prior trials.
Moving to slide 25, I remind everyone of the data Julian presented regarding improvements in NT-proBNP and six-minute walk tests, and further highlight that these improvement characteristics are almost twofold higher than what has been observed in prior trials. Finally, on slide 26, we connect the dots between stabilization and clinical outcomes using our internal trial data set. For the sake of time, I'll focus only on box four, where for the first time, we look at correlations between key outcomes with continuous variables and serum TTR levels on drug. In an exploratory post hoc analysis of the relationship between on-treatment serum TTR levels and on-treatment measures of CVH, NT-proBNP, and KCCQ, there is an association between the mean on-treatment TTR level in each of these three variables.
This suggests that restoring serum TTR to mid upper values of the reference range is associated with better outcomes at the subject level. All figures in box 4 have a P value of less than 0.0001 for the correlation test. The line in each plot represents the least squares linear best fit. Okay, I'd like to wrap up then quickly with next steps. On slide 28, you can see that we anticipate, we continue to anticipate filing our NDA by end of year. On slide 29, I'll just remind you briefly that these data being presented today represent an exciting starting point, not an ending point, for further data analysis and generation. In particular, we're quite excited for what is to come at AHA, so please stay tuned for that.
With that, I will turn the discussion back over to the operator for questions.
Thank you. If you'd like to ask a question, please press star one, one. If your question has been answered and you'd like to remove yourself from the queue, please press star one, one again. Our first question comes from Salim Syed with Mizuho. Your line is open.
Great. Good morning, guys. Congrats on the additional data. A few from me, if I can. Number one, just on safety. I know there's been a lot of focus on efficacy over the course of the last couple of days here. Just curious if there's anything notable on safety as you look at acoramidis and tafamidis. Both look pretty clean. I'm just curious if there's anything there that you guys see that we should pay attention to?
Yeah. Oh, yeah, I can take that and then come back to you for.
Sure, sure.
Yeah, I think, to your point, both of these drugs are remarkably safe. We haven't seen, as Dr. Gillmore suggested, anything that causes us concern. One of the things that's been interesting in the patient data for it is there was a bit of focus with tafamidis on the imbalance in falls and erectile dysfunction. Those are point estimates, so one doesn't know how important that might be. But on our study, hearteningly, that actually was reversed, and the point estimate favored treatment, both in terms of falls and in terms of sexual or erectile dysfunction.
Okay. Got it. Thanks, Neil. The other questions I wanted to ask here, up to... So just one, just on slide 14, we've gotten a few questions on this. It seems like the arms inverted on the all-cause mortality and then flipped back again. So it looks like they inverted kind of around month 14 or so, and then they flipped back. Just curious, what was the dynamic there that caused for that, dynamic, I guess? And then on the, on the last question here, on the time to improvement for NT-proBNP in the six-minute walk, is there anything you can tell us for the patients that do see an improvement in those measures? When did they improve? And, and perhaps what was the, the mean improvement, if, if you can give us that information. Thank you.
John, do you want to take this?
Yeah, sure. Hi, it's Jonathan Fox here, Chief Medical Officer. I'll try to take a stab at your question about the KM curves. So in order for the Cox proportional hazards model to hold to complete fidelity, the slopes of the lines would have had to be constant. And obviously, they're not. They kind of, you know, there are steep sections, and there are relatively flat sections. And so if you were to, in a way, even though this wouldn't statistically be an appropriate thing to do, but in your mind's eye, you could sort of redistribute all those deaths so that they happen at a more constant rate, so to speak. And then those, in order to flatten out those lines or pull them into more of a constant slope.
And, you know, the final result is the final result. One interesting aspect of this is that because the lines cross, according to your correct observation, in fact, the Cox proportional hazards model has been violated in terms of the assumptions that go into it, which is, as the name of the test implies, it assumes that the proportional hazards of the two different arms are, in fact, constant over the entire duration of the trial, and obviously, they're not. So, yeah, the result is what it is. I mean, everybody in this sort of endpoint analysis expects to see a KM curve according to a Cox proportional hazards.
But in fact, we did go back because of the assumptions not holding, we went back and applied a couple of other sensitivity analyses using some other nonparametric tests that yielded, you know, a consistent result, is what I can say about it.
Yeah, maybe just to build on that, I think, when you're referring to a few questions I also got from some investors about, like, could that be the action of tafamidis dropping? No, it's a super low-end occurrence. So as John said, the data are the data, but there's nothing that you can ascribe to some action associated with drop-in. There's low levels of drop-in, as you remember from my JPM comments around that time. And certainly, we don't actually at any time see the tafamidis on population outperforming the acoramidis on population in terms of mortality, so. And what was your second question again, Selena?
Yeah. Thanks, guys. Thanks, Jonathan. Yeah, on the question on NT-proBNP and six-minute walk, just given the notable improvement in a significant portion of the patients, just curious, when did these patients actually see that improvement? At what time point in NT-proBNP and six-minute walk? And what was the mean or median, whatever you can give us, quantification of that improvement?
Yeah, both great questions. So I mean, interestingly, on six-minute walk distance, obviously, improvements were only shown once we had enough degradation on placebo, which obviously, were well after about 12 months, as we all know, for the first part. And then, on the second piece, you do see this immediate separation, associated with NT-proBNP, which I think is quite heartening, Jonathan.
Yeah, just one point of clarification. Those measures of improvement from baseline were made at the month 30 time point. So obviously, it only applies to those people who made it to month 30.
Got it.
Whoever dropped out because of death or some other reason were not included in that assessment.
Understood. Okay. All right. Thank you so much, guys. Congrats again.
Thanks, Salim .
Thank you. Our next question comes from Tyler Van Buren with TD Cowen. Your line is open.
Great. Hey, guys. Thanks for the thoughtful presentation, as always. Dr. Gillmore, do you think tafamidis would have shown similar results on mortality if tested in this exact same population? And as a follow-up to that, given the acceleration and separation of the mortality curves in the last six months, do you think it's possible that acoramidis could show a greater long-term mortality benefit in the OLE than what tafamidis even showed in ATTR-ACT if we follow these patients another six to 12 months? And after those two, just finally, I would love to hear early feedback from ESC, from your colleagues, what it's been like.
So, to early feedback, I'll take the questions in reverse order. Early feedback from the ESC colleagues is extremely positive. And I think, you know, most people were very, very impressed by the data, as it were. In terms of your second question, yes, I do think that we may see the survival, you know, improving in terms of the open-label extension and potentially see survival that is, you know, that is better than one would, you know, that we see with tafamidis. But as you already are aware, the survival, you know, the overall survival of 81% at 30 months is already better than anything that we've ever seen previously.
And your third question was about whether we would, if we treated patients in this, you know, if we treat patients with tafamidis, this group of patients with tafamidis, would we see the same results? I certainly don't think, for example, we would see a statistically significant difference in all-cause mortality alone. You know, so what I'm essentially saying is, one would, I expect to see reasonably similar results, although, you know, as we've heard, it may well be that the results from ATTRibute-CM would be better in the current, you know, if compared to tafamidis, if we compare them in the current population.
Thanks very much.
Thank you. Our next question comes from Tom Schrader with BTIG. Your line is open.
Good morning. Congratulations. Thank you for taking the question. Kind of a related question to Dr. Gillmore. Based on what we've seen for tafamidis and acoramidis, are most of your colleagues now believing these drugs are different? Is that very much in flux? What do you think the best data are that they are different?
I think that it's a little bit early to say. I mean, the principle, you know, of stabilization is certainly one that colleagues are becoming increasingly aware of. And the fact is that the principle of increased stabilization resulting in increased serum TTR, resulting in increased benefit, if you see what I mean, that correlation, that relationship, is something that, again, colleagues are becoming increasingly aware of. So I think that, you know, that provides powerful evidence, if you see what I mean, in terms of molecular mechanism for the benefits that we're seeing in this trial.
Is that better than an NT-proBNP in the minds of your colleagues?
I think they're very different. I mean, NT-proBNP is a useful biomarker for looking at, you know, progression or otherwise of clinical disease. Serum TTR is a little bit early to be, you know, to base a trial purely on the increase in serum TTR. But, you know, one can foresee that in several years' time, it might be that one can base a trial on TTR, you know, the raise in serum TTR as an early indicator of TTR stabilization.
Got it. And then a quick follow-up for Neil. Sounds like you're itching to do a head-to-head trial. If you did a head-to-head trial with 1,000 patients, with what you know about the two drugs for 30 months, is that big enough or is it even bigger than that?
With what endpoint?
Clinical endpoints, cardiovascular hospitalization and mortality.
I mean, from what we know, it would likely be slightly bigger than that if you just were going to go mortality and CVH. I think the key here is to have, and we continue to do this, strong look at our data and try to identify subpopulations and endpoints whereby you could actually, you know, actually run the trial in a reasonable amount of time. We haven't determined precisely what that looks like, but as I said, you know, we're engaged on that topic.
Great. Thank you.
Yeah, thanks.
Thank you. Our next question comes from Paul Choi with Goldman Sachs. Your line is open.
Thank you, and good morning, and congratulations to Neil and team on the study results again. My first question is for Dr. Gillmore, and I was wondering if you could share if you and any of your colleagues, you know, have thought about, you know, which particular patient populations acoramidis might be most beneficial in. I think one of the results that stand out is the benefit in the mutant population, which was not seen with tafamidis. And so I was just wondering if you could maybe comment on how you and your colleagues may be initially thinking about segmenting patients for the various therapies. And then I had a follow-up question.
I mean, to be completely honest, one would want to give acoramidis to all patients with ATTR amyloidosis at this stage, and it's as simple as that. I think that, you know, obviously, patients with hereditary ATTR amyloidosis and polyneuropathy, you know, one may want to consider, you know, the RNA interference therapeutics. But for patients with ATTR amyloid cardiomyopathy, which constitutes the vast majority, one would, you know, currently want to give acoramidis to all of them, regardless of stage, regardless of genotype. You know, that's how I would be thinking about it.
Okay, great. Thank you. And then for Neil and the team, can you maybe comment on how you're thinking about the shape of the label and what specific claims you'd be, you'd be looking for? And then for the ex-US filings in 2024. Are there any particular gating factors, or is it just prioritizing the US filing first?
Yeah, two great questions. I'll be brief on them. In terms of label, obviously, that's work that's ongoing, and we'll need to see, you know, what the discussions look like with the agency. But I think the label will look very similar to the TAF label. I think, if not, you know, exactly the same in terms of different numbers, but very similar verbiage. And we're talking about, yeah, the impact on the combination of mortality and CVH. And as Dr. Gillmore raised, that we had a stat sig impact on those, on that two-factor win ratio as well. So I think these things will be very similar. And yes, to your second question, it is just about, we're a small team.
We're trying to go as quickly as possible to get this drug out into the U.S. markets, hopefully sometime, you know, Q3 of next year. But we'll just have to see what the regulatory turnaround looks like, and we wanna follow that as quickly as possible with an EMA filing sometime in 2024. I think it's important to note that, you know, and with having Dr. Gillmore here, we were extremely privileged to work very closely with a wide variety of sites in Europe. The dynamics of the trial when we kicked it off were such that we prioritized a broader and more international study than certainly, I think other sponsors have.
And so we see it as our responsibility in turn then to bring the drug as quickly as possible to all of those geographies. So, yeah, we're working hard at it. I don't think there'll be much of a gap between the two.
Got it. Okay. Thanks, Neil. Congratulations again.
Thanks, Paul.
Thank you. Our next question comes from Mani Foroohar with SVB Leerink. Your line is open.
Hey, guys. Congrats on the data. Obviously, a lot of questions around, some of the key endpoints. I was hoping to get into patient population a little bit. Are there differences in baseline characteristics or in, you know, or in how diligently these patients were following standard of care, compliance, et cetera, between those patients in, with tafamidis dropped in and those not? You know, like, you know, any difference that we should be looking into between those two populations, those who had dropped and those who didn't, before we start drawing, internal conclusions comparing tafamidis versus acoramidis, for example?
Yeah, not really, Mani. We haven't seen anything yet, and it's hard to do a super rigorous study when you have 16% or, you know, around that. But it looks pretty well-balanced, you know, as you would expect from the randomization. There weren't anything that was, that, you know, in terms of NYHA class or anything like that, that would have biased those results. You know, in terms of the overall patient population, as Dr. Gillmore pointed out, it was a slightly healthier population. You know, but given the staging criteria that we used as compared to the ATTR-ACT trial, but that was as expected from whom we could enroll.
Then, you also observed the imbalance of tafamidis on placebo versus on drug, which I think is important to note. John, do you wanna add anything?
Yeah, just one other point to make that I think might contribute to a better understanding of your. And to answer your question. You know, the only thing we really could control was nobody was allowed to be on, to drop in on tafamidis up to 12 months. Beyond that, we had no control over who dropped in, when, during their journey through the trial they dropped in, and, you know, and how sick they might have been at the time they dropped in versus. You know, randomization only works at randomization. So, you know, things that happened later on in the trial, you can't control.
Great. That's helpful. And then one follow-up. The question I've gotten from a few different people, is: So you are guys, as you mentioned, a relatively lean team. How do you think about, you know, potential, you know, capital requirements to the launch? You know, how do you think about partnering strategy? I know you talked about partnering or capital or addressing capital at the, Analyst Day with Century Royalty, in January. How has your thinking evolved around supporting this launch and getting the most out of this drug, getting it to the largest number of patients possible?
Yeah, it's a great question, Mani. And I think, you know, at a high level, principles to apply to the question are twofold. Number one, we wanna work with and believe we can be the best owner of this compound, but if there are other parties that help us, for instance, get it internationally, more quickly and with greater access to patients that need it, we're certainly all ears for that. And then secondly, on the, in the context of capital, as you well know, we're always seeking the lowest cost of capital to continue to finance the company, through its valuable funding points, which are several over the course of the next 24 months, and not just limited even to this program in ATTR cardiomyopathy.
I think, you know, that being said, we think there's probably an incremental close to $600 million needed for us to finance to profitability. That's actually extraordinary because of the fact that this market is quite large in, in ATTR-CM, and the ramp can be quite, quite quick. So we'll look at a variety of different things to layer in that capital over the course of, of, of the coming couple of years as, as we launch this product and, and, and get through the three other phase IIIs we have going on in ADH1, LGMD2I, and achondroplasia.
Great. Thanks for taking the question, guys. Congrats again.
Yeah, thanks, Mani.
Thank you. Our next question comes from Ellie Merle with UBS. Your line is open.
Hey, guys. Thanks so much for taking the question, and, congrats again on the data. Maybe just for the cardiovascular hospitalization data, what proportion of the cardiovascular hospitalization events were from heart failure visits? And I guess, how do you view the inclusion of the urgent heart failure visits? O f potentially affecting the comparison of your hospitalization results to tafamidis, where those were not included in their phase 3? Thanks.
Yes. So we haven't really, you know, dug into this data as deeply just yet, as we'd like to. So I don't really have a firm answer for you today. Given the nature of this disease under study, you would expect most of them to be heart failure hospitalizations. And often, though, if they're triggered by new-onset atrial fibrillation, for example, that would be encoded as the reason for hospitalization, even though the need for hospitalization in the context of new-onset AFib, for example, is probably, you know, tightly coupled to the fact that these are people with heart failure. Somebody with a normal heart who experiences an episode of AFib, you know, they may well be treated in the emergency department and discharged to home.
So, we, you know, in the coming weeks and months, we will be digging into the details of those sorts of analyses and plan to publicize those in due time.
Sorry, I don't think I was clear, just the urgent heart failure visit component, of the CV hospitalizations. Sorry.
Oh, you mean the events of clinical interest? Those actually were a very, very small proportion of the total CVH, single-digit percent.
Okay, great. Thanks. That's helpful. And then just a follow-up: In the Class III patients, have you guys said what the breakdown was on the effect on survival in that subgroup? Thanks.
No, we'll be releasing that data and other classes and then other analyses associated with the trial at AHA and other conferences to come, so didn't want to give it all away at once.
Understood. Thank you.
Thank you. Our next question comes from Dane Leone with Raymond James. Your line is open.
Hi, thank you for taking the questions, and thanks to Monty for asking the obligatory partnering question, so I don't have to. So, the biggest debate coming out of this weekend and that ESC is obviously, you know, the cross comparison to Tafa and how you guys position this product. And, you know, as you said on the call, we don't have to rehash, you know, it limits the cross-trial comparison, especially to something given this complexity.
But what I do think is an important debate point, that, you know, maybe will get answered at AHA and maybe you can opine on a little bit now, is with the ACM curve and some of the, you know, lack of stability in the proportional hazard ratio over the time course of the study, there has been questions on when we see that time to first cardiovascular hospitalization curve, is that gonna look consistent throughout the study? And if it does, does it give you an angle of more comparability to ATTR-ACT in some form or fashion? If it doesn't, is that something that the clinical community is going to need additional data or explanation on?
You know, then finally, just in your view, is that the right cardiovascular metric to really be focused on when we're looking between the two studies and relative benefit rates? Thank you.
Yeah, I think time to first event is a great area to focus on. And I think stay tuned for AHA for more information on that. Yeah, no, I do think, Dane, it's a really nice analysis to do, and I think it will help clinicians to understand how to weigh these agents against each other. You know, and I will emphasize that, you know, we are caveatting all this stuff, cross-trial comparisons, which I think is important. And you know, we see this as a large unmet need that we get you know work with several different sponsors on.
I was at a conference, just a couple days before ESC, where a large pharma CEO was talking about the concept that typically, as more sponsors come into a space, especially a space that's underdiagnosed and with as large an unmet need as this, the market just continues to grow and the opportunity to help patients continues to grow as well. So, you know, while we're focused on this being a more profound stabilizer, we're equally as focused on just trying to get a playing field as quickly as possible and giving physicians choice.
Thank you.
Thank you. Our next question comes from Greg Harrison with Bank of America. Your line is open.
Hey, good morning. Thanks for taking the question, and congrats again on the data.
Thanks.
So given that you've shown survival and cardio hospitalization rates approaching that of normal people in that age group, do you think you're nearing the limit of clinical benefit that could be achieved with the stabilization approach?
Yeah, that is the point of doing the actuarial analysis, is to say what, you know, what is possible. If our best guess is what the, you know, the best this drug can do is effectively to operate on the pathology associated with ATTR cardiomyopathy and nothing else. So, yeah, I do... I agree with your premise that there's probably not a whole lot more headroom available.
Okay, great.
For this or any other agent, right? The point estimate can vary a little bit around here, but we're getting to the point here where it's very, very close to kind of what you can do.
Okay, great. Then, on the primary prevention trial, could you just talk a little bit more about the rationale there and how you would expect data from that trial to add to the profile of acoramidis?
Yes, Jonathan here. So, you know, we kind of have to kind of take two, two steps to the side here and, and cover a couple of important aspects of the study population, the patient population that we want to study. First of all, I just made a mistake and called them a patient population, because they're not patients. They're asymptomatic carriers of pathogenic variants who are members of an identified family, and within the pedigree, there are affected family members who have developed either variant-associated cardiomyopathy, variant-associated polyneuropathy, or a mixed phenotype. And, you know, you try to put yourself into the shoes of an individual, just, you know, for the purposes of this discussion.
You know, a characteristic participant in the trial would be, depending on the variant and its associated age of onset, it would be a young or middle-aged adult. And they're, they have, by the objective criteria applied at screening, have no objective evidence of either of the polar opposite phenotypes or a mixed phenotype. But you know, if you put yourself into that person's head, it's they know that they're a carrier. They know that their first and second-degree relatives have gone on to develop devastating progressive disease, and they're frightened, and they're worried. And many of them will, you know, come back every other year to the clinic to be evaluated.
But then they're saying, "Well, hang on, why, why do I have to wait until I get symptomatic disease? You know, isn't there something you can do for me now?" So the point of the trial is to say, well, you know, if we actually do take those people who are- who have no evidence of disease, who are presymptomatic, and randomize them to blinded therapy or with acoramidis or placebo, can we, in fact, reduce or eliminate that onset of disease? So the endpoint is the development of objective criteria of either cardiomyopathy or polyneuropathy. And at that point, they would exit the trial and be invited to go to an open label extension. So, you know, fast-forward to, you know, what's the goal here?
The goal here is to develop a new indication that says acoramidis is indicated for the prevention of ATTR, any phenotype, in variant carrier symptoms.
Got it. That, that's helpful. Thanks again.
Thank you. Our next question comes from Anupam Rama with JP Morgan. Your line is open.
Hey, guys. Thanks so much for taking the question, and congrats on the update.
Thank you.
If I remember correctly, the Class three NYHA patients in the tafamidis study ATTR-ACT didn't really show a favorable benefit in the subgroup analysis on CV hospitalizations, but clearly acoramidis did on this subgroup analysis. Maybe for the company and Dr. Gillmore, like, how do you put that data point into context of potentially population differences enrolled, as well as, you know, how that might impact your treatment practice decisions in more severe patients? And then a second question. Access has been an issue with tafamidis and a hurdle to get to patients. Dr. Gillmore, maybe you can talk about, have you ever had this experience in the UK, or maybe what do your global colleagues express frustration with this? And for the company, remind us of how you're thinking about strategies to address the access concerns.
Thanks so much.
Yeah, I can frame it up, and then I'll pass it over to Dr. Gillmore to expound on this with much more expertise than I could. Yeah, the point estimate, it's hearteningly, you know, in the right direction for class three CVH, which was not observed, as you mentioned, in the ATTR-ACT trial. I will mention that the confidence interval does pass unity there. So, you know, the signals are consistently stronger as you go earlier, and that's consistent with what we've seen in the ATTR-ACT trial as well. But yeah, it is great that the point estimate is going the right way here. And maybe I'll ask Dr. Gillmore to add on anything there.
Well, exactly as you said, the point that it's heading in the right direction. I think this is probably a factor of power rather than, you know, absence of efficacy necessarily in the situation.
And then, your second question was on access. Oh, I'll pass that over to, you know, do you have access to tafamidis?
We don't have access to tafamidis in the U.K., and we are still in a situation where we don't have access to tafamidis.
For the company, what are your strategies to address the access concerns, sort of, in the U.S. and other regions?
Yeah. So we've been doing a great deal of work on this. As we've said from the get-go, our goal really here is to provide access as broadly as possible, as quickly as possible. I think the optimization data, actually, a new sponsor helps us to make a credible story to HTA authorities, and we're working on the HEOR story as well. But we're going to move as quickly as possible and try to gain access in all the geographies worldwide.
In the U.S., obviously, there's a changing dynamic associated with IRA, and there's also much that can be done, as we look at, you know, what other sponsors have and haven't done in terms of improving access and improving a physician's ability to write the drug for a patient. And so we'll be employing some of those strategies that you see mostly in other therapeutic areas, as we commercialize products.
Thanks so much for taking the questions and congrats again.
Thank you. That's all the time we have for questions. I'd like to turn the call back over to Neil Kumar for any closing remarks.
All right. Well, thanks everyone for taking the time today, and as I mentioned, stay tuned for further data releases at AHA in the months to come. Thanks again for your interest.
Thank you for your participation. This does conclude the program, and you may now disconnect. Everyone, have a great day.