OK, good evening, everybody. So Dr. Watellis was very directive to all of us, saying that we're going to be on time. So I have three hours to tell you about and unpack a full symposium. How do I open? Do I just click on my? Oh, yeah, just click on your desktop. All right. Now you've got two hours, 59 minutes. OK. So for the next two, I'll make it early, two hours and 58. So I want to applaud you all for staying here this evening. I know it's been a long day. So I want to thank you all for your attention. So I really want to, I think we're ending this terrific symposium. And the goal for my talk is really to give you a taste of what's on the horizon and what's to come. And clearly, this is not going to be comprehensive. So I'm cherry picking a few things that I think are really going to be next up, OK? And then just to kind of give you an idea of what to expect, really, over the next two to five years. But indeed, there are a number of really exciting things on the horizon, even beyond that. So this is the outline of our discussion. So I'm really going to separate this into two broad categories. I'm going to highlight some promising diagnostic advances for ATTR, and then we're going to shift gears, and we're going to talk about some really novel treatments for ATTR that are really on the approximate horizon. And I'm going to be very careful not to overlap very much with Dr. Amberdecker's talk. So what we're going to discuss first are some AI-based tools to look at ECGs to screen for ATTR amyloidosis. Then we're going to pivot to some really novel ATTR-specific blood biomarker developments. And we'll also discuss some highly sensitive PET and SPECT-based amyloid tracers. So I think we've all heard this evening that there are some really terrific ATTR tests out there. You've heard a lot about how to incorporate this into your clinical practice and how to really put it together. So we know there's blood work, you've seen on a lot of the question stems, antiprobian P, troponin, ECGs, we actually haven't heard a lot about that tonight. Come on, guys. Echocardiography, we haven't heard much about MRI, but it is a great tool. You've heard about bone radio tracer scintigraphy, and then, of course, you've heard a lot about endomyocardial biopsy. So what is the first tool that I think will be transformative in the way that we diagnose this disease? Now, this really doesn't enhance the way we diagnose this disease, but as many of you will find, and I know many of us up here share the opinion that really the rate-limiting step of diagnosing ATTR amyloidosis is just, hey, asking yourself the question, could my patient even have this disease? And so this is one of several tools that is now being developed, which uses an AI algorithm to give a risk score that tells us how amyloid-like an ECG is. Now, these are data from the Mayo Clinic, and it is gonna be further validated in a big multicenter study, so we will see if this will be eventually approved for diagnosis, but is currently promising, and hopefully this will aid in finding cases that would otherwise be undiagnosed. Now I wanna pivot to the other end of the spectrum, and we're gonna talk about a novel PET radiotracer. So iodine-124-epizamotide, or ATO1, is a panamyloid peptide that binds directly to amyloid fibrils. So if you look at this histological specimen, or if you look at the figure on your screen, you'll notice that there are two pictures on your screen. If you focus on the one to the right, you will see that this is a Congo red-stained myocardial specimen, and then you are looking at successive slices of the same specimen, and you will see that biotinyl-labeled epizamotide also localizes with Congo red, which demonstrates that this peptide binds to amyloid. So when we add radioactive iodine to it, you can see that this gives us exquisite PET-based imaging pictures. So these are data from a very small pilot study which demonstrates one key thing, in that you do not see uptake in controls, but now if you look at individuals with clinically manifested ATTR amyloidosis, clearly it's positive. We can see cardiac uptake, and if you look at the whole body, you can see extracardiac uptake. And now it also offers the hope, if you look at the column with individuals that have no clinical manifestations, that is the clinical negative, this at least supports the hypothesis that we can detect very, very early amyloidosis in individuals that might not yet manifest with some of the red flags you heard Dr. Davis speak about earlier. And what about blood tests? We all use blood tests all the time. Now there are a number of blood tests currently being developed for the detection of amyloidosis, but one specifically that I would like to share with you is something called TAD-1. Now I don't have TAD-1 up here on the screen, but that's what these investigators call it. So this is a peptide probe that binds to one of the amyloid forming regions of the fibril. Now if you look at the picture on your left-hand side, you can see that this peptide is highly selective for amyloid fibrils, and it really does not bind to any controls, either monomeric TTR, tetrameric TTR, or a number of other amyloid-based controls. Now what happens when we measure this in the blood of individuals? This is from a convenience sample, and you can see that these levels are very, very low in individuals that do not have amyloidosis. Now what you do see is that individuals that are carriers do have low but detectable levels of this peptide that binds to these circulating amyloid aggregates, and then if we look at the pre- and post-treatment, you can see that it even responds to treatment, suggesting it might detect early disease in the blood and might even be a marker of treatment response. And if you look at the panel on the right, you can also see that it is not elevated to a great degree in patients with AL. And now for the last several minutes of this talk, I want to pivot to some novel ATTR treatments on the horizon. So Dr. Amberdecker has really gone over this table in great detail, and you've heard a lot about it, but I think this really gives you a history lesson of where we've come from. So largely before 2018, as you saw in his timeline, we were using medications that were off-label, that may have had some data, or maybe data that really wasn't all that supportive, but it was largely all that we had to offer treatment. Then if you look at the current state of where we are, you can see now we have a number of terrific options that are currently approved for individuals with ATTR, cardiomyopathy, and neuropathy, especially on the heels of the recent FDA approvals of Aciramidis and Vutriciran. So now I want to pivot to what we are going to look for in the future, and again, this list is not entirely exhaustive, but these are the most proximal things that you'll be hearing about in the near future. And the first thing I'd like to talk about is Aciramidis, which as you heard from Dr. Amberdecker, this is not a novel therapy in that it is more so a way, a novel way of using this therapy. So this is currently being tested in the ACT early clinical trial, which is very unique in that they are randomizing individuals at risk for developing ATTR amyloidosis who carry pathogenic alleles. And so what they're doing is they're randomizing these individuals to Aciramidis or placebo, and then they are being followed clinically and on study protocol to assess for the development of either ATTR-CM or ATTR-PN. And now I want to transition to Eplantracin. You've heard a little bit about it earlier this evening. So Eplantracin is a second generation antisense oligonucleotide, and this leverages what is called a GalNac ligand that binds to an azeologlycoprotein receptor on hepatocytes. And this molecule features really terrific stability and it has great potency and it can be used over the long term. In fact, this is given subcutaneously every month. So it is currently FDA approved for the treatment of ATTR polyneuropathy, and this is largely based on the results of this clinical trial, where you can see for individuals with ATTR polyneuropathy, it does halt disease progression. Now, I'm happy to say that the cardio transform clinical trial has currently on follow-up. It has been completely enrolled now for several years, and hopefully we will see a favorable readout very, very soon, so stay tuned. And now I want to pivot to a very novel treatment that leverages CRISPR-Cas9 single base pair editing technology to permanently silence the TTR gene. And I'm gonna butcher the title, so bear with me. Nobody's ever told me how to say it, but Nexigoran Xiclomerin. We're just gonna call it NexZ. So this is a CRISPR-Cas9 treatment that is delivered intravenously, and it circulates in the bloodstream by a lipid nanoparticle that then gets reabsorbed in, or gets absorbed in the hepatocytes by ApoE, and then binds to LDL receptors to get endocytosed into the nucleus. Now, what is novel about this is this is given as one infusion, right? As opposed to dosing something monthly or taking pills on a daily basis, this could offer the hope for a completely sustained response that will be long-lasting. Now, these are data from a phase one clinical trial that demonstrates a dose-dependent response on TTR knockdown after just one single infusion. And this agent is currently being tested in the magnitude clinical trial, which is enrolling individuals with ATTR-CM. And now the last agent that I wanna discuss is called ALXN2220, or NI006. So this is a very, very novel treatment. So you've heard a lot about disease stabilization or halting progression. This agent offers the hope of disease regression, or even using the C word, cure. So what you're looking at here, so these are murine samples that have amyloid engrafted. And these mice were given doses of this monoclonal antibody. And you can see here that given that there was a dose-dependent response in ATTR reduction. So these monoclonal antibodies, very interestingly, were found by combing human B-cell libraries. Again, which really highlights that there might be some patients that are actually amyloid immune. And this has very, very high affinity binding to ATTR. And what these monoclonal antibodies do are that they activate macrophages to then go attack, and then it clears amyloid through phagocytosis. So these are data from the phase one clinical trial. And what I'm gonna show you are some pretty compelling results to look at cardiac amyloid load, either by bone scintigraphy and cardiac MRI. And what you can see here is that after just four months, it appears that there is regression or improvement in these metrics by lower uptake and lower ECV. This is an MRI metric that we use to assess amyloid load in the heart. And then when we extend these data out to 12 months, notice that there is an even greater reduction, suggesting that longer and repeated exposure to this agent may be better, and again, supports the hope for amyloid improvement. So these pictures really hammer home the idea. Now, you can see here that this individual on the top row was given this agent at baseline. And you can see that the enhancement, or the radio tracer uptake in his myocardium improved and was sustained. Now, if you look at an individual that received placebo, notice that as soon as he was given the active agent, we start to see regression of uptake in his myocardium. This too is currently being tested in a phase three clinical trial. So in summary, novel AI-based tools, biomarkers, imaging tests on the horizon really all have the potential to transform the diagnostic process for ATTRCM. And then hopefully I've given you a taste that the therapeutic landscape is rapidly changing. And there is really an ever-growing promise that this disease is really being transformed, and that the natural history of these individuals will be different than it was when we were all in medical school, and we were all learning about this disease. So that's my last slide, and I just want to point out to Dr. Watellis, I was just three minutes short of three hours.

ATTR amyloidosis

AI algorithms

CRISPR-Cas9

Aciramidis

monoclonal antibody