Good afternoon, everyone. Thank you so much for joining us here today. My name is Richard Chang. I'm a heart failure cardiologist at the University of Washington. I'm very honored on behalf of the ACC to give this talk on the current and emerging treatments in TTR cardiomyopathy. So over the next 15 minutes or so, I really want to drive home two key objectives. The first is we're going to talk about targeted treatments for TTR cardiomyopathy. As you'll see, there's a lot of emerging therapies over the last several years, and there's quite a few more in clinical trials. And then we're also going to talk about the role of heart failure GDMT for this cohort, since this is a common question, because a lot of our patients will have heart failure. So from the concept of current therapies for TTR amyloid, it really recapitulates the underlying biological mechanism. Many of you are very familiar with this figure, but what we know is that the liver makes the TTR protein. The TTR protein is normally a tetramer, and it serves a normal function in the body of transporting thyroxin as well as vitamin A. However, in certain individuals, either due to genetic variants or due to aging, this protein will destabilize. When it destabilizes, it then will misfold into dimers and monomers, and if your body is unable to clear this, then it will become amyloid deposits, which will frequently go into the heart, and when it goes to the heart, it results in stiffening of the myocardium and it restricts the phenotype. And in addition to that, for many types of the wild-type TTR, this will also go into tendons, and this is why we often see the red flags, for example, of carpal tunnel syndrome, as well as trigger finger. For individuals with variant TTR, there's a high tropism, typically for the nervous system, so many of these individuals will also have involvement with peripheral or autonomic neuropathy. As I mentioned, nicely, many of our treatments are targeting this pathway in different places. So first, on the far left here, we have our TTR silencers or knockdown agents, and this includes the antisense oligonucleotides, the small interfering RNAs, as well as CRISPR technology, which many of your patients are probably going to ask you about. A little bit more downstream, we have our TTR stabilizers, and these are currently the FDA approved treatments for TTR cardiomyopathy. This includes tefamidase, which was the first drug approved for treatment of TTR cardiomyopathy, and very recently, acromidase also received FDA approval for this indication. We also have diflumasol, which is a historic treatment, is an off-label use of it, NSAID, and is not used much in the contemporary era, since we have more effective treatments. So both these silencers, as well as stabilizers, it really abrogates the downstream formation of TTR amyloid by preventing either the production of TTR or by preventing the TTR tetramer from falling apart and making amyloid. Very excitingly, recently, we have the advent of additional therapies with these depletors. These are currently in clinical trials. So what they do is these tend to be monoclonal antibodies. The thought process is, while our other therapies really prevent progression, is there a way for us to reverse the disease process? And the idea is that these depletors will bind the amyloid deposits either in the heart, the tendons, or the nerves, or remove it, and it will result in the reversal of the disease process, and patients will improve as a result of these therapies. So in terms of the trials for these therapies, the original trial was the TRACK study, which looked at the use of tefamidase 20 versus 80 mg versus placebo. The primary analysis was with the Finkelstein-Schoenfeld method, which is a nonparametric method looking at Wnt ratios. But what this study showed is that tefamidase, which again is a stabilizer, compared to placebo, reduced the composite endpoints, and in addition to that, it resulted in a significant reduction in all-cause mortality, as you can see here. Despite this, even though tefamidase is very effective in reducing mortality, there's still a 30% residual mortality. So this is a very beneficial treatment for our patients, but does not prevent progressive disease completely. Because of this, there's a lot of interest in other therapies, which may be additive or as alternatives. So what do we know in terms of these other therapies? Since ATTRACT, there was the more recent Attribute-CM study, and I think the point here is that there's a changing landscape in TTR. We're diagnosing our patients earlier because there's increasing awareness over the last several years. And as you can see, the ATTRACT study was published in 2018, and the patient accrual was prior to that. With Attribute-CM, this is a study with acromatase, this was published in 2024, but includes a more contemporary cohort. And as you can see on the bottom here highlighted, these patients in a more contemporary era tend to be less sick. In other words, they are MYJ class 1 or 2 in most instances, and they're less likely to be MYJ functional class 3. Additionally, these patients have a lower median NT-proBNP. And what we're moving towards and seeing is that now we're diagnosing patients earlier and earlier in the disease process. So going back to the Attribute-CM study of acromatase, this was a study looking at acromatase compared to placebo in a 2-to-1 randomization schematic. And they used a Finkelstein-Schoenfeld method looking at a 4-step primary hierarchical analysis of all-cause mortality, cardiovascular hospitalization, NT-proBNP, and 6-met walk distance. In this trial, acromatase was superior to placebo for this 4-step hierarchical outcome with a win ratio of 1.8, as you can see on the bottom right here. So when we look at the individual endpoints, acromatase reduced the risk of death from any cause, as you can see from this cumulative incidence curve on the left. And in addition to that, it reduced the decline in functional capacity as measured by the KCC-Q questionnaire. Despite this, however, we still have some residual mortality of about 20%. And in addition to that, from a quality of life standpoint, while acromatase mitigated the reduction in quality of life, it did not prevent the reduction completely. So this goes back to the concept of all therapies are very effective, but is there room for improvement? Because of this, there is a lot of interest in incremental therapies or alternative therapies. So this is a slide that summarizes these other therapies and classes of therapies. So we have our silencers, which includes Particiran, Ritriceran, and Epilontericin. And then we also have CRISPR, which again, you're going to hear quite a bit about I'm sure from your patients. And then the concept of these depletors, which are anti-amyloid antibodies, which may potentially reverse the disease process. So the question is, how can we achieve TTR knockdown? We have our small interfering RNAs with Particiran and Ritriceran. We also have our antisense oligonucleotides with Inotericin and Epilontericin. While the exact mechanism of these therapies are not the same, the effect is very similar in that they both result in TTR messenger RNA degradation. And by doing so, this prevents the production of TTR protein. However, because this acts very downstream on the messenger RNA, you have to redose with both of these therapies. For this reason, there has been a lot of interest in CRISPR as an alternative technology. What CRISPR is, it's gene editing technology and induces a double-strand break in the TTR gene with a frame shift mutation, preventing the production of the protein. Because this edits the gene directly, the thought is that this will be a single-dose permanent solution for preventing production of TTR. So what data do we have on TTR knockdown in silencers? We have data from the HELOSPEED trial, which was looking at the use of Ritriceran in patients with either variant or wild-type TTR chrotomyopathy. In this study, patients were randomized one-to-one to Ritriceran versus placebo every 12 weeks with a composite endpoint of death from any cause and recurrent cardiovascular events. As you can see on the right here, Ritriceran was superior to placebo in preventing these endpoints. Currently, Ritriceran is undergoing FDA review for the specific indication of TTR chrotomyopathy. So there is a lot of interest in CRISPR, which is in vivo gene editing, and patients are going to ask you about this frequently. So current TTR knockdown with the small interfering RNAs and with antisense oligonucleotides is based on the degradation of TTR messenger RNA. The challenge with this is this is limited by the need for ongoing administration. What I mean by this is that you have to re-dose your patients sequentially. In addition, there is some concern for potential side effects of these therapies over time. Or your patients could develop a resistance to these therapies or potential for an infusion reaction, for example. The reason why TTR amyloid is a very exciting target for CRISPR-Cas9 is that TTR amyloid is a monogenic disease. As a result, you only have to target a single gene. The TTR knockdown also has limited additional physiological effects. So TTR knockdown tends to be very well tolerated without other systemic effects. Additionally, because a TTR protein is made in a liver, this can be targeted by lipid nanoparticles. And this is a very complex slide, but I'm going to show this to you because I think it's important to understand the underlying mechanism of a CRISPR. So this is from a seminal paper from Julian Gilmore and colleagues, and I strongly encourage you to look this up at the New England Journal website because they explain it much better than I can. And they have a nice video showing how CRISPR works. But what CRISPR is, is this is essentially a gene editor, which is packaged in NTLA-2001, which is a lipid nanoparticle delivery system with high liver tropism. And it delivers the messenger RNA with a Cas9 protein and a single guide RNA that contains a TTR gene-specific sequence to the liver. This is uptaken by the haplocytes and then results in a sequence-specific cleavage of the TTR gene with a frameshift mutation, reducing production of functional TTR. And at least in the early phase 1 studies, this appeared to be well tolerated. What you can see here in data from the phase 1 study, and this is now renamed NexZ. So this is a combination of the CRISPR-Cas9 in combination with the lipid nanoparticle. What this did is this resulted in significant knockdown of TTR serum levels very quickly, and this was sustained up to 24 months in a phase 1 study. This is currently in the phase 3 study with a magnitude 2 trial. So there's more to come, but at least in this phase 1 study, this appears to potentially be a durable solution with a single dose extending to 24 months. So what I've shown you so far really falls within the classic paradigm of heart failure, right? As a heart failure cardiologist, what we think about is our patients have progression of the disease process to advanced heart failure, for example. And typically for heart failure patients, we give them heart failure GDMT with the hope that we can reverse the disease process with these compensatory mechanisms and decrease in the neurohormonal activation. Similarly, for amyloid patients, many of the therapies that we have so far, the stabilizers as well as the silencers, really prevents progression. Both of these classes of medications will slow down progression of disease, but does not truncate progression completely, and these drugs do not reverse the disease process. So the emerging paradigm in amyloid is whether we can reverse the disease process, and I think that's what's so exciting about these anti-amyloid depleter therapies, right? Because now, in addition to slowing down the disease process, the question is can we give our patients these monoclonal antibodies, which bind and remove the amyloid and result in a reversal of the disease process? So what data do we have in this? This is a phase one trial of NI006, which is a monoclonal antibody against TTR protein. This has since then been renamed Alexion 2220 because it was acquired by Alexion. But in this phase one study, they looked up 40 patients randomized to NI006, which leads to phagocytosis of TTR fibrils, but not of normal folded TTR. This is with an IV infusion every four weeks. At least in the phase one study, this tended to be well tolerated. And this slide shows some representative examples. On the left here, we have images of cortex scintigraphy, and on the right, these are pictures of cortex MRI and extracellular volume. What you can see on the left here for our patients, over time, there was a decrease in uptake of the radionucleotide tracer. And what you can see is the heart gets much lighter over time. So this appears to be removing the amyloid deposits in the myocardium. On the right, in terms of extracellular volume, this is also decreasing over time, suggesting that there is removal of the TTR deposits. This is from the phase one study. However, currently, these monoclonal antibodies are in phase three studies with the depletor study, and there's a second study which is going to start shortly from novo-nordisk with another monoclonal antibody. So going back to this concept of unmet needs and additional therapies, we know that the stabilizers, both tefamidase and acroaminase, are currently FDA approved for our patients. What about these silencers? With partistiran, unfortunately, this was not approved by the FDA. However, Onilam is no longer seeking FDA approval because vitreosiran is a new generation silencer which targets a similar mechanism. Vitreosiran is currently FDA approved for TTR variant polyneuropathy, and it's undergoing FDA review for TTR cardiomyopathy, and the decision is anticipated to come out in March 2025. eplantorcin remains in clinical trials, and we should hopefully have the results from this shortly, but it's another TTR silencer. With the CRISPR technology, it's in clinical trials with a magnitude trial for gene editing that's completing enrollments. And then I mentioned on a prior slide, we have the alexon2220, which is currently in a phase 3 clinical trial. And then PRX004 is the monoclonal antibody, which is going to be entering clinical trials shortly by Novo Nordisk. So now that we've talked about targeted therapies, I'm going to move on and talk a bit about our second objective, namely the use of heart failure GDMT for our population. So in order to understand why we think heart failure GDMT may impact our patients with TTR amyloid a little bit differently than our other patients with heart failure, we really have to understand the physiological mechanism of what's happening in our patients. So these are pressure volume loops, which I'm sure many of you remember, but essentially what happens here in gray is these are our idealized normal individuals. The colored lines are our patients with TTR amyloid, blue is wild type, red and green are patients with variant TTR. Our ESPVR line shifts downward and to the right. Our EDPVR line, which is a marker of diastology, moves upwards and to the left. In addition to this, our patients have abnormal ventricular vascular mismatch with an altered arterial elastin slope as represented by this dotted EA line, which is going to be altered in our patients with TTR amyloid. What this does from a physiological standpoint is our patients will have a lower stroke volume and this is why we often say our patients with advanced TTR amyloid are going to be heart rate dependent. Additionally, our patients have higher filling pressures because this EDPVR line is shifted upwards and to the left, for any given volume, our patient will have a higher LV filling pressure and because of this, our patients will have restrictive physiology. Additionally, our patients will have ventricular vascular mismatch because of this altered EA slope and this is why afloat reduction in our patients may not be as effective in augmenting their stroke volume. So moving on to the specific classes of neurohomoblockade, what do we know about beta blockers? As you know, this is still a little bit discordant in terms of whether we should or should not be using beta blockers in our patients with TTR amyloid. This is data that we published from the Columbia University looking at the use of beta blockers versus no beta blockers and what we found is that for the total cohort, there was really no difference in outcomes. However, if you looked at patients who were de-prescribed beta blockers upon follow-up, for patients where we stopped beta blockers, they appeared to do better than patients that were continued on beta blockers. So although there appeared to not be much benefit for the total cohort, perhaps stopping beta blockers for patients with side effects may be beneficial. What about data from other cohorts? This is data from the UK NAC of a larger cohort and a more contemporary data set, but again for the overall cohort, there was really no difference in outcomes for patients on beta blockers compared to those not on beta blockers. However, when these patients were stratified for patients with ejection fraction greater than 40% compared to patients with ejection fraction less than 40%, there was no benefit for patients with EF greater than 40%. However, in those with EF less than 40%, beta blockers appeared to show a benefit. So the question is, how do we make sense of this discordant data, right? In both cohorts I showed you, at least for all comers, there did not appear to be a benefit for beta blockers compared to no beta blockers. However, in the UK NAC cohort for patients with low ejection fraction, there appeared to be a significant benefit. This may have something to do with the beta blocker use as well as the patient cohort comparatively in these two data sets. So when you look at this, the UK NAC cohort used mostly bisoprolol, while the Columbia cohort, most patients were on creveille or metoprolol, and this partly has to do with the US versus the use of bisoprolol in Europe. Additionally, the doses of beta blockers were lower in the UK NAC cohort, where the average dose of bisoprolol was less than 2.5 mg per day. Additionally, the patients in the Columbia cohort tended to be sicker. When you look at this, there were more patients with variant TTR, including individuals with polyneuropathy. More patients have pacemakers or ICDs. More patients were MYHA functional class 3 or 2.4, and patients had lower blood pressure at baseline. So it's possible that perhaps for beta blockers, if we target patients who are a little bit less sick with low doses of beta blockers with reduced ejection fraction, they may have some benefits. What about ACE numbers and ARBs, right? Well, it turns out in both the Columbia data set as well as the UK NAC data set, there was no benefits comparing TTR amyloid patients on ACE numbers or ARBs compared to those not on ACE numbers or ARBs. So it's a little bit unclear whether we should be putting our patients on ACE numbers or ARBs. And this may have to go back to the fact that these patients, if you after reduce them, they may not have as much augmentation or stroke volume because of our underlying physiology. What about MRAs? It turns out that MRAs may be beneficial in patients with TTR amyloid. So on the left here, this is data from a post hoc analysis of Topcat that Brett Sperry published. So he looked at cohort enriched for amyloid based on a reduced S-prime velocity and a increased intraceptal wall thickness on echocardiogram. These patients were not adjudicated specifically for their diagnosis of amyloid, but featured their suspicions for amyloid. And what he found is that for these patients that were enriched for cardiac amyloid, there was a significant benefit for patients on MRAs compared to patients not on MRAs in the Topcat data sets. For the UK NSE data set on the right here, they also showed that there appeared to be a benefit for MRAs compared to no MRAs. So what about our last pillar of heart failure GDMT for SOT2 inhibitors and TTR amyloid? So we know that from clinical trials for the broader heart failure cohorts that this is beneficial across a full spectrum of ejection fraction, including in patients with heart failure with preserved ejection fraction. This is data from an observational study from 14 referral centers for TTR amyloid where they propensity matched patients on SOT2 inhibitors compared to patients not on SOT2 inhibitors. In this study, they showed that SOT2 inhibitors were very beneficial in patients with TTR cardiomyopathy. SOT2 inhibitors appear to reduce all-cause mortality as well as heart failure hospitalization. Additionally, it slowed the decline in EGFR, the attenuated increase in NT-proBNP, and it reduced the need for loop diuretics. And we know from other studies that loop diuretic dose is a good surrogate for worsening outcomes in TTR amyloid. In other words, SOT2 inhibitors appear to be very beneficial for our patients with TTR cardiomyopathy. So how do we put all this together, right? So let's say you confirm the diagnosis of TTR amyloid in your patients. So we want to manage heart failure. In general, you should probably be putting your patients on SOT2 inhibitors as well as MRAs based on this retrospective data sets. The use of beta blockers is a little bit more questionable. And then we don't have much data shouldn't benefit with acembers or ARBs. You can put your patients on loop diuretics if you need to decongest your patients. You should manage the arrhythmias for your patients for TTR. Additionally, what about targeted therapies and disease modifying agents? I think this is where we have the most emerging data. So for your patient with wild-type TTR cardiomyopathy or variant TTR cardiomyopathy, currently the FDA-approved treatments are stabilizers with tefamidase or acaromidase. I mentioned earlier that ritrusiran, which is a TTR silencer, is currently undergoing FDA review, although we may know shortly whether it's approved or not for this indication. For your patient with variant TTR neuropathy, the two TTR silencers, ritrusiran and eplantersin, are both FDA-approved for the indication of polyneuropathy. For your patient with a mixed phenotype or variant TTR, you can use any of these agents. I mentioned earlier, we have a number of other exciting therapies which are currently in clinical trials, which includes eplantersin for cardiomyopathy, depleters, as well as CRISPR. So what are our take-home points? So what do we know? There are two main strategies which have been proven to be effective for treating TTR cardiomyopathy. The stabilizers are already FDA-approved, and your patient should probably be on one of these therapies, either tefamidase or acaromidase. We know that TTR knockdown appears to be effective. Ritrusiran was shown to be beneficial in the HELOS-B trial and is currently undergoing FDA review specifically for the indication of TTR cardiomyopathy. Eplantersin is in clinical trials for the same indication. For heart failure GDMT, I'm not going to overdrive this point home, but we know that spironolactone and estrategic numbers are beneficial. I showed you the data earlier. You should consider use of beta blockers, perhaps at low doses for less sick individuals based on the UK NSE data. So what don't we know? I think what's problematic is we don't really know which therapy is most effective. Right now, since the TTR stabilizers are what's FDA-approved, this is not so much as an issue as when newer therapies are approved, we don't really know which class of therapy is going to be most effective because there is really no head-to-head comparison across the different drug classes for the target therapies. We also don't know whether we should be combining therapies. Obviously, there is some concern from a cost standpoint, but separate from that, we don't have great data showing whether combination therapy is beneficial to monotherapy. I mentioned earlier there's a lot of excitement for these depletors because it may reverse the disease state, and these are currently in trials. For CRISPR, this may be a single-dose durable solution for our patients, but this is still in clinical trials. And I think importantly, we always worry about potential barriers to access, but we also worry about the cost implications of therapy, not only for individual patients, but for our healthcare system as a whole, as many of these therapies are very expensive. I thank you very much for your attention.

TTR cardiomyopathy

targeted therapies

TTR amyloid

CRISPR technology

clinical trials

heart failure GDMT