Good afternoon, everyone. My name is Richard Cheng here at the University of Washington, Seattle. I have the privilege today of giving you this talk on the treatment of transthyretin cardiac amyloidosis as part of a series of talks from the American College of Cardiology. I highly encourage you to view the rest of these talks because I think they all contain critical information. This slide provides a nice framework and overview of how we manage patients with cardiac amyloid. On the left, these are general management strategies from a medication standpoint as well as a rhythm standpoint for patients with cardiac involvement of amyloid. In the middle, these are specific treatments for light chain amyloid, but we're not going to talk much about this since these are generally managed by our oncology colleagues. And on the right, these are specific treatments for TTR amyloid, which we're going to focus on today. So I'm going to start by providing an overview of traditional heart failure guideline directed microtherapy, and you're going to see that data is somewhat limited for what we can use on these patients. I'm going to move on and talk a bit about arrhythmias in patients with cardiac amyloid, and I'm going to end by talking about specific treatments for TTR amyloid. This is a paradigm of natural clinical progression in TTR amyloidosis that we proposed about a year and a half ago. We believe that there is a preclinical phase where these patients may be identified very early. For example, these are patients who incidentally have amyloid deposits after carpal tunnel surgery in the tenosynovial tendon, and it's unclear whether intervention at this point may lead to improved outcomes. After this, these patients enter the early clinical phase. Here, this is really where we want to identify patients because earlier initiation of treatment will result in improved outcomes. In general, this is where we want to start considering therapies such as diuretics to alleviate fluid overload. Additionally, TTR stabilizers may be beneficial here. There was a recent study in Jack Carter Oncology where they showed starting to found this on patients with TTR amyloid before overt clinical heart failure resulted in improved outcomes. If patients are diagnosed later, they may then enter the restrictive heart failure phase. This is more problematic as patients will frequently have a waxing and waning clinical course where they have a declining clinical status with hospitalizations improve afterwards, but then may be re-hospitalized. Here, this is when we want to start heart failure medications, although data is somewhat limited in terms of how effective these are. If patients are not diagnosed until very late, they may have end-stage heart failure. For this, there's very little data in terms of how effective medications are, including we're not sure how effective TTR stabilizers are. We don't know whether heart failure medications work. We have limited data on inotropes in these patients and heart transplant can be considered, but in selected patients. I put this slide here because I think it's really important to understand the physiology of these patients by looking at pressure volume loop to understand why patients with cardiac amyloid do not tolerate traditional heart failure therapies. If you recall here on the bottom, this is your EDPVR line. In these patients, it's shifted upward and to the left. For any given volume, there is increased LV filling pressure. On the upper left here, this line represents your ESPVR line and it's shifted downward and to the right. In these patients, contractility is also reduced. This dotted line here, it represents the arterial elastin slope. In these patients, this is altered. Because of this, these patients have abnormal ventricular vascular mismatch. What we see here is in gray. This is a normal individual. These colored lines are various patients with TTR amyloid. Blue is wild type, red is V122I, and green is T60A. What we can see is that these patients with cardiac amyloid will end up having a decreased stroke volume. This explains why they don't tolerate beta blockers, for example, because of this fixed low stroke volume. In addition, this abnormal ventricular vascular mismatch explains why these patients do not tolerate vasodilation. Normally with vasodilation, we expect patients to augment their stroke volume, but because of this abnormal ventricular vascular mismatch, these patients are unable to augment their stroke volume and they can become hypotensive with afterload reduction. I'm going to start by talking a little bit about everyone's favorite drug with digoxin. As you know, the use of digoxin in patients with cardiac amyloid is somewhat controversial on whether it can be safely utilized. On the left, we have a single center study from the Mayo Clinic looking at 107 patients with light chain amyloid. In 91% of patients, the indication was for rate control for atrial fibrillation flutter, which is why digoxin is most commonly used in these patients. On follow-up, 50% of patients stopped digoxin based on physician preference. As you can see, only 11% of patients had significant arrhythmias and only 5 patients had terminal arrhythmias. A more recent study from the Cleveland Clinic had similar findings. This was a more mixed cohort of 42 patients with TTR amyloid and 27 patients with light chain amyloid. Again, we see that the majority of patients were on digoxin for rates control and less patients were on digoxin for heart failure. In this series, 12% had digoxin-related arrhythmias or toxicity, and no deaths were attributed to digoxin. So, a conclusion is that in these patients, digoxin may be considered with rigorous patient selection and close monitoring of digoxin levels and renal function. Next, I'm going to move on and talk a bit about beta blockers. As you know, the use of beta blockers in patients with cardiac amyloid is also somewhat controversial. So, this is survey data from 11 Italian centers on patterns of beta blocker therapy prescription. In this study, included 642 patients with cardiac amyloid with mixed light chain and TTR amyloid, and included information from the first and last beta blockers. So, this is a study that was conducted in a first and last visit on medications. As you can see, the majority of patients on beta blockers at baseline were on them for arrhythmia management for either atrial fibrillation or ventricular arrhythmias. Similarly, patients started on beta blockers doing follow-up were started on them for arrhythmia reasons. As you can see, only 33% of patients were continued on beta blockers during the study. 43% were never on beta blockers. And interestingly, 19% stopped beta blockers, the majority of which stopped them due to worsening heart failure. I think one natural question is whether beta blockers impact outcomes. And there's very little data on this. In order to fill the gap, we performed the single center study looking at 309 patients with TTR amyloid from Columbia University. As you can see from this figure on the left, there was really no difference in survival for patients on beta blockers compared to not on beta blockers. And this is a direct adjusted survival curve. However, on the right, what we see here is for patients who were de-prescribed beta blockers doing follow-up, the majority of which was for worsening heart failure. Patients who stopped beta blockers appeared to have improved survival compared to those patients that continued beta blockers. So in general, what we would recommend is to consider stopping beta blockers on patients who are symptomatic from them. In this study, the results were consistent regardless of looking at beta blocker use with baseline use, time-varying use, or using an IPTW-weighted analysis. In the same study, we also looked at the use of ACE inhibitors or ARBs in patients with TTR amyloid. What we found is there was no difference for patients on ACE inhibitor and ARBs versus patients not on ACE inhibitors and ARBs from a survival standpoint. We also looked at the use of MRAs in these patients. Again, we found no difference in direct adjusted survival for patients on MRAs compared to those not on MRAs in this cohort. However, a more recent study from Dr. Brett Sperry and colleagues used TopCat to look at the use of MRA in possible cardiac amyloidosis. So many of you recall for TopCat, this was a randomized clinical trial looking at the randomized clinical trial looking at patients with ejection fraction of greater than or equal to 45% and heart failure with preserved ejection fraction randomized to spironolactone versus placebo. In this study, Dr. Sperry enriched the cohort for patients with likely cardiac amyloid by taking patients with S-prime velocity of less than or equal to six centimeters per second on echo and a septal wall thickness of greater than or equal to 1.2 centimeters. What they found is whether patients were enriched or not enriched for cardiac amyloid, there appeared to be a significant improvement in survival for patients on MRA compared to those not on MRA, as you can see from this figure on the right. So here, for patients enriched for cardiac amyloid in red, what we see is for patients on spironolactone, they appear to have improved survival. On the prior slides, I provided you with a lot of data regarding the use of heart failure therapies in patients with cardiac amyloid. So the question is, how do we put all of this together? This is a nice table that was recently published, which summarizes recommendations from the various guidelines in terms of what to do with heart failure medications. First, for loop or thiazide diuretics, in general, it's recommended across all the guidelines because it can decongest your patient that's volume overloaded and improve them symptomatically. For beta blockers, most of the guidelines recommend that beta blockers should be avoided or be used very cautiously, as patients will often not tolerate this due to their fixed stroke volume. For acinibators and ARBs, similarly, they should be avoided or used very cautiously. If you recall from the pressure volume loop, these patients are unable to augment their stroke volume when they have restrictive filling. And what will happen is in some of these patients, they may become hypotensive when you try to vasodilate them. For saccubitrile valsartan, there's limited data. So most guidelines do not have a recommendation, but the AHA guidelines places this in the same category as acinibators and ARBs, and that they should be avoided because it can result in hypotension. And for MRAs, this category has the most mixed recommendations. As you saw, there's some signal of benefits based on the retrospective analysis of TopCat. Across the guidelines, they recommend potentially using MRAs in conjunction with loop diuretics if there's adequate blood pressure and renal function, because this is favorable for potassium sparing and because of some signal of benefit. Lastly, what about SGLT2 inhibitors? There's very little data on the use of SGLT2 inhibitors specific for TTR amyloid. But I can tell you, clinically, we tend to use this based on the HEF-PEF indication, and patients tend to tolerate it. We are going to move on and talk about the management of arrhythmias in patients with cardiac amyloidosis. First, atrial fibrillation is very common in these patients. In particular, for patients with wild-type TTR amyloid, the prevalence of atrial fibrillation may be as high as 70%. Amyloid can also infiltrate the conduction system, leading to advanced heart block. Since amyloid also deposits in the atria, this can lead to atrial standstill and increase the risk for atrial thrombus, particularly in conjunction with atrial fibrillation. And we all know that amyloid infiltrates the ventricles, and this can increase the risk for ventricular arrhythmias. This single-center study from the Mayo Clinic nicely highlights the increased risk for atrial thrombus in patients with atrial arrhythmias and cardiac amyloid. So in this study, they looked at 29 patients with TTR amyloid and 29 patients with light-chain amyloid with atrial arrhythmias referred for cardioversion. When they performed transesophageal echocardiogram, 13 of the 58 patients had left atrial appendage thrombus. This included two patients in atrial fibrillation for less than 48 hours and four patients who had therapeutic INR for greater than three weeks. What you can see on the right is for patients with cardiac amyloid in blue compared to patients without cardiac amyloid in red, the rates for cancellation for cardioversion were higher in patients with cardiac amyloid, the majority of which were canceled due to presence of intracardiac thrombus. So the take-home message from this is we should consider anticoagulating our patients with cardiac amyloid and atrial arrhythmias regardless of other risk factors. In summary, for managing atrial arrhythmias and amyloidosis, there are several points we should consider. First, these patients have very high rates of atrial fibrillation, so you should always be monitoring for this. Second, you should anticoagulate your patient with cardiac amyloid and atrial fibrillation regardless of CHA2-VASc score because their rates for intraatrial thrombus is much higher than other cohorts. Third, we don't have much data on left atrial appendage closure in these patients, so this should only be considered in patients with contraindications to anticoagulation. I mentioned earlier that the use of digoxin should be done with caution and with close monitoring if you have to give it to your patient for rate control. And lastly, if you have to use an antiarrhythmic, amiodarone tends to be well tolerated. We know that rates for ventricular arrhythmias are also higher in patients with cardiac amyloidosis because of amyloid deposits in the ventricles. However, we have limited guidance in terms of what to do for these patients. These are recommendations from the 2017 AHA-ACC-HRS guidelines for managing these patients. Whether ICDs are effective for primary prevention for sudden cardiac death is uncertain, but many deaths do not appear to be preventable by an ICD. And the reason for this is historically we have felt that some deaths are driven by PEA rather than ventricular arrhythmias. Because of this, decisions must be individualized because data remain too limited to allow formal recommendations. I can tell you clinically, we have a lower threshold to consider ICD for primary prevention in patients with light chain amyloid, more so than TTR amyloid, as light chain amyloid patients appear to be at higher risk for sudden death than patients with TTR amyloid. So how do we put this together for heart failure therapies for cardiac amyloid? So what do we know? We know that loop diuretics can alleviate symptoms. Beta blockers are not well tolerated in advanced cardiac amyloid due to restrictive filling and ventricular vascular decoupling resulting in hypotension. Atrial and ventricular arrhythmias are very common and you should always anticoagulate your patient with atrial fibrillation and amyloid. Heart transplant is a viable option in carefully selected patients. However, despite what we know, there are many areas for research. We need more data on other heart failure guideline-directed medical therapies. For example, we need data on the use of SHLT2 inhibitors in patients with amyloid. We are unsure whether there is any benefit of ICDs for primary prevention in cardiac amyloid beyond the standard recommendations for other patients with heart failure. And lastly, we don't know what the ideal patient selection is for heart transplants. How do you balance patients that are too well with those that are too sick? Because of the advent of targeted therapies, we're able to treat these patients more effectively. So it's harder to know when to refer a patient for heart transplant in the current era. Now that you're all experts on managing heart failure and arrhythmias in patients with TTR amyloid, we're gonna talk a bit about targeted therapies. This is a very elegant strategy because it follows natural biologic targets. So we all know that the liver makes the TTR tetramer and this is usually nicely bound. However, either due to a genetic variance or because of aging, this becomes unstable, dissociates and makes monomers. When the monomers misfold, it can then form amyloid fibrils, which sticks to various organs, such as the heart, leading to amyloid cardiomyopathy. So we have several strategies which have been shown to be effective. First, we know that you can suppress TTR synthesis. Historically, this was done with liver transplantation. More recently, we have a silencer with particirin and an antisense oligonucleotide with inotricin, which knocked down TTR production. CRISPR also acts in this fashion, which I'll touch on briefly. We also know that TTR stabilizers can be effective for these patients, particularly with tefamidase based on the TRACT trial. And tefamidase is the only FDA approved agents for TTR cardiomyopathy. AG10 remains in clinical trials and diflinosol is a non-selective NSAID, which is sometimes used in these patients. What about more downstream? Can we disrupt the oligomers or can we degrade amyloid? There's been a lot of interest in this. As you can see here, there's various compounds, but all of these have either limit data or they remain in studies at this time. So currently we only have suppression of TTR synthesis and TTR stabilization in terms of managing these patients. I am going to start by talking about stabilizers since this is the only FDA approved treatment for TTR cardiomyopathy. So if you recall, TTR is a tetramer and the crystal structure of tefamidase, which is a TTR stabilizer, binds to TTR at the T4 binding site. By doing so, it prevents dissociation of the tetramer into monomers. This is data from the very important ATTRACT study, which was a randomized clinical trial of patients on tefamidase compared to placebo with TTR amyloid. The primary analysis was done with the Finkelstein-Schonfeld method, which is a non-parametric method to weight the endpoints based on Wnt ratio and the order of clinical importance. In this study, patients were randomized to tefamidase 20 milligrams versus 80 milligrams versus placebo, keeping in mind that the bioequivalence of tefamidase 80 milligrams in the study is equivalent to Vindamax 61 milligrams, which is currently commercially available. What they showed is there was a 30% relative reduction in all-cause mortality, and the number needed to treat was 7.5 over 30 months. So tefamidase significantly reduces mortality in patients with TTR amyloid. This slide shows the forest plots for pre-specified subgroup analysis. What you can see is for survival, results were consistent regardless of hereditary versus wild-type TTR, MYH functional class, and dose of tefamidase in this study. However, for hospitalization in general, the signal was also consistent across the various subgroups. But what we see here is that for patients who are MYH functional class three, they appear to have increased rates of hospitalization. This is unlikely to be driven by a worsening patient population disease status, but rather this is because patients survived long enough to be hospitalized. So this again underscores the importance of early detection and early treatments in patients with TTR amyloid. This slide shows the long-term outcomes from the ATTRACT study. What happened in the study is at the end of the study, patients on placebo were cross-overed onto tefamidase as part of the open-label extension. And there are several key take-home points from this. The first is that there was a 41% reduction in the relative risk for mortality for those on tefamidase compared to those on placebo. Second, looking at patients on placebo that then crossed over onto tefamidase, there was a reduction in mortality compared to this line extrapolated based on what would happen if patients remain on placebo from a gamut distribution model. Third, what this shows is early initiation of tefamidase will lead to improved outcomes. Again, overall, even though some of these patients later on will transition from placebo to tefamidase, patients on tefamidase the entire time have better outcomes. Lastly, median survival for those on tefamidase is 53% at five years, which is arguably similar to other heart failure cohorts. So even though we used to say amyloid is a very bad disease with current therapies, it may be similar to other patients with heart failure from a survival standpoint. Moving on in our framework of targeted therapies for TTR cardiac amyloid, we're gonna talk about suppression of TTR synthesis with a focus on silencers and antisense oligonucleotides next. Our data on both silencers as well as antisense oligonucleotides are from polyneuropathy trials for patients with hereditary TTR polyneuropathy. So what we know is from the Apollo trial with Particirin and the Neuro TTR trial for Inoturicin, there was a reduction in polyneuropathy in these patients on therapy. However, we also have non-randomized data specific to TTR cardiac amyloid cohorts. A post hoc analysis of Apollo with Particirin showed a signal of cardiac benefit with a decrease in wall thickness, improved strain and decreased NT-proBNP with a 46% reduction in cardiovascular hospitalization or mortality. A single center open label study with Inoturicin in patients with TTR cardiomyopathy showed a decrease in LV mass, decreased BNP and improvement in six minute walk. This leads to phase three randomized clinical trials of these agents in TTR cardiomyopathy. So with Apollo B, this randomized patients with TTR cardiac amyloid to Particirin versus placebo. The preliminary data was recently presented by Dr. Matt Maurer at HFSH 2022. What they found is for TTR cardiomyopathy patients, there was an improvement in six minute walk, improved KCCQ and a reduction NT-proBNP and troponin. There are also randomized clinical trials with second generation agents with Cardiotransform with Epilontericin, which is a second generation antisense oligonucleotide and with Helios B with Vitruceran, which is a second generation RNA silencer. But the results from these studies are not yet available and the studies are ongoing. I'm going to move on and talk a bit about CRISPR because there's so much excitement around this technology and patients ask about this constantly. So I think the first thing to understand is that current TTR knockdown is based on degradation of TTR mRNA. However, this is limited by the need for ongoing administration therapies and the potential of side effects over time. CRISPR-Cas9 is in vivo gene editing with a single guide RNA. And the reason why this is so attractive for TTR amyloid is that TTR amyloid is a monogenic disease to target a single gene. TTR knockdown has limited additional physiologic effects and TTR is mostly made by the liver. And because of this, this can be targeted with lipid nanoparticles. This slide shows the use of CRISPR-Cas9 with the NTLA-2001 lipid nanoparticle delivery system with liver tropism that delivers messenger RNA with a Cas9 protein and a single guide RNA to knockdown TTR production. I highly encourage you to look at the New England Journal of Medicine websites because there's a nice video on this which can explain this technology much better than I can ever do. But essentially what happens is that this lipid nanoparticle is taken up by the hepatocytes and results in sequence-specific cleavage of the TTR gene. This results in a frame shift mutation that prevents the production of functional TTR. In this original pilot study, treatment was completed in all six patients with grade one reactions but no significant adverse effects. More recently, Dr. Gilmour presented updated data from the phase one study at the American Heart Association 2022 meeting. In this study, there were 12 patients who received a single infusion of the NTLA CRISPR molecule at either 0.7 or 1.0 milligram per kilogram. There was a greater than 90% TTR reduction at 28 days which was sustained to four to six months. In general, this was well tolerated with a single serious adverse events and some infusion-related reactions. There are key considerations here. First, this would theoretically be a single treatment with long-term silencing, so it has favorable implications for adherence and costs and is one of the reasons why patients are so interested in this. However, this was a small end and limited follow-up time, so additional data is needed. Historically, there were concerns for genome toxicity or oncogenic effects, although the preclinical data has shown that this approach is precise. We have talked so far on the use of stabilizers and silencers in terms of preventing progression of disease. What about removing what's already there? So I'm gonna touch briefly on the use of targeted therapies for oligomer disruption or amyloid degradation. There have been many compounds developed for this purpose. However, as you can see from this systematic reveal, we have insufficient data to recommend any of these. Most of these compounds have been studied in limited small retrospective studies, and some of them remain in early phase trials at this time. However, there's much interest on what we can do for the deposits already there. So the question is, how do we put all this together since there is so much information? So taking our patient with confirmed TTR amyloid, we started by talking about how to manage heart failure, and as you saw, there's limited data on many of the heart failure therapies, and you have to be cautious with using them. We then talked about managing arrhythmias and key considerations, such as anticoagulating your patient with cardiac amyloid and atrial fibrillation. We then ended by talking about disease-modifying agents. Currently, the only FDA-approved treatments for TTR cardiomyopathy, whether it's wild-type or variants, TTR is with tefamidus. However, if your patient has variant TTR polyneuropathy, then you can consider the use of inotricin or perticarin. I think what is very exciting in the field is there are many other agents which are currently in clinical trials that we talked about, and hopefully the data will be out soon, and we're hoping that this will benefit our patients. These are our take-home points for TTR-targeted therapies. What do we know? We know that there are two main strategies proven to be effective for treating TTR amyloid. For patients with variant TTR polyneuropathy, you can silence production with perticarin or inotricin. For patients with TTR cardiomyopathy, whether it's variants or wild-type, the only FDA-approved treatment is to stabilize the TTR protein with tefamidus. There remain many areas for research. First, what do we do when we get better at diagnosing asymptomatic patients? For example, the patient with carpal tunnel syndrome and amyloid deposits in the tenosynovium, but not elsewhere. When is the earliest we should start treatments in these patients? Second, will TTR sensors work for TTR cardiomyopathy? The Apollo B study has shown promise, and if sensors do work, should patients be treated with a combination of TTR sensors and stabilizers, or sensors or stabilizers alone? Third, will CRISPR-Cas9 be a durable and safe solution for our patients? Lastly, are amyloid degraders and extractors going to be effective at removing amyloid deposits? Regardless of the answers, I think there remains another key question regarding the high costs of these therapies at this time. And I think another area of research is how we can best implement these therapies to treat our vulnerable populations. I'm going to end here, and I want to emphasize that for managing cardiac amyloid, it takes a multidisciplinary team, not only of cardiologists, but the involvement of other subspecialties as well as the entire cardiovascular team. If you have any questions, please feel free to reach out to me.

transthyretin cardiac amyloidosis

heart failure therapy

arrhythmia management

TTR stabilizers

SGLT2 inhibitors

ICDs

CRISPR-Cas9