 So good morning everyone, first correction for the day, my last name, three letters, but it's pronounced how. We will, I'm sure that was an excellent talk. Dr. Warner, thank you for that. And we will reserve the questions towards the end. We move on to our next speaker. Dr. Julia Rosenthal is from Mayo Clinic and a good friend. She's an advanced heart failure cardiologist. She's a local and national expert in this field. So we will be talking about treatment of amyloidosis. Dr. Rosenthal. Good morning everybody. It's a pleasure to be here with each of you. I'd like to start by thanking the organizers for putting this together. I would have never expected so many individuals in the room so I'm glad everyone's excited about amyloid. I've been tasked to talk about treatment for amyloidosis and to think, you know, just over five years ago we had nothing. What did we have? We had palliative care, pastoral care, but now we actually have some therapies. So I'm curious if you want to just show a raise of hands in the room, how many of you have actually prescribed an therapy for treating someone with amyloid? So a few prescribers. How many of you cared for amyloidosis patients? All right, how many of you not cared for an amyloidosis patient? Couple, all right. So hopefully by the end of the day, moving forward, you're all going to make the diagnosis of amyloid and whether or not you start a therapy, hopefully you'll feel more comfortable making that diagnosis and triaging, who do you call next? Cause we all need friends. All right, here are my disclosures. So with that, we're going to recognize treatment stretch for amyloid and figure out how do we apply these disease targeted therapies? And lastly, I'll just give you a preview to some upcoming clinical trials. So I think it's important to understand where we've been and know where we're going. As we already heard from Dr. Warner earlier today, the actual amyloidosis was described more than 150 years ago by Dr. Verkow as that starchy material. And then moving forward, we had our very first intervention for individuals living with hereditary TTR amyloidosis. We thought about transplanting, meaning liver transplant, our hereditary patients, but we knew we needed to do better. And thanks to our colleagues such as Dr. Kelly and other individuals who really pioneered or galvanized the field of thinking about therapies, not only for TTR amyloid but AL amyloidosis, we've subsequently had a number of things that have been established throughout time. Our first treatment for hereditary polyneuropathy was launched with a silencer called Patizoran back in 2018. Shortly thereafter, followed by Inotircin. And then finally we had our first TTR therapy in the form of a stabilizer for our cardiac patients with the Feminis. And subsequently in 2021, we had our very first sort of FDA approved for AL amyloidosis deritunamab, a monoclonal antibody against plasma cells. More recently, we had Patizoran make the scene, another silencer, and we just had a hot off the presses of Plano-Tircin, our fourth silencer for hereditary polyneuropathy. So with that, I'm gonna spend most of the morning talking about therapies for TTR amyloidosis. I'll then allude just briefly to some therapies for AL amyloidosis and sort of what's to come. So with that, I'd like to start with a case just to get you all excited. This is a patient of mine, 65-year-old gentleman with hereditary amyloidosis, 380-ALA, so of Irish descent, who had a known history of heart failure and pretty symptomatic, as you can see, with markedly elevated cardiac biomarkers. At the end of the day, it's the cardiac factors that drive the morbidity in both of our patients with TTR amyloidosis as well as primary amyloidosis. He also had neuropathy, not uncommon of a mixed phenotype in someone with 380-ALA. I don't know how to go back, I apologize. So it was an echocardiogram, hopefully you just appreciate it very thick. There we go, thank you. With that classical apical sparing strain pattern, as you heard about already from Dr. Warner. Moving forward, you can see the Technizium pyrophosphate scan was performed. It had a significant uptake, grade three, so that sort of pinkish signal is brighter than bone. Classic for a positive scan, and this gentleman had the absence of a monoclonal protein, which is critical if you're thinking about amyloidosis. So out of curiosity, how many in the room would do, what would you do next? Knowing this background, how many of you would order a silencer? Nobody? How about a stabilizer? Couple of you? How about send for a clinical trial? None of you, okay? How about combo therapy? All right, refer for advanced therapies. Couple of you, excellent. So let's continue. But I'd like you to think about this, because at the end of the day, nobody really knows about combo therapy yet. Hopefully some data will be coming thanks to a few clinical trials in process. Clinical trials, definitely we should be thinking about it. That's how all of these drugs came to be, as you referred your patients to clinical trials. But let's move forward. I want you to take a moment and just look at this cartoon. It was taken from the European guidelines, and it starts with the liver. As you can see, the majority of our trans-thorian protein, or that tetrameric TTR, is actually made in the liver. Other parts of the body that make TTR include the choroide plexus, as well as the parts of the retinal epithelium. But the majority is made in the liver. And this is the key step, is you have this tetrameric protein here. But it's the critical step of the unfolding that Dr. Kelly and team at Scripps really identified. That unfolding steps lead to these dimers, and then monomers, and then the amyloid fibrils. And it's those amyloid fibrils that are very sticky, and they will deposit in places that they do not belong, and ultimately lead to organ dysfunction. Whether it's cardiac failure, renal issues, nerve issues, GI, malabsorption. Remember, amyloidosis has no boundaries. So that's true for AL amyloidosis as well, but I just wanted to focus on TTR for a moment. So then we think about where can we interfere with the production of the amyloid fibrils? And there are multiple different pathways, as you can see in this cartoon. So we start at the very beginning of TTR production. Is there a way we can suppress the formation of that TTR tetrameric protein? And in fact, we used to think about liver transplantation. I think that's really gone out of vogue nowadays thanks to the advent of these therapies, like silencers and stabilizers. But that was the cornerstone of therapy 40 years ago, almost. What about gene editing? Perhaps each of you have kind of seen on the scenes the CRISPR-Cas9 therapy that was published a couple years ago. Phase three clinical trial is in progress of magnitude, very exciting times. And then we have the silencers, really preventing the formation at the level of translation. And now we have four FDA-approved silencers that includes Patiziran, Inotircin, Vutiziran, and most recently off the presses, Aplanotircin, that really suppress about 90% or more of that tetrameric protein formation. Moving forward, what about that critical unfolding step? I already mentioned, this is what Dr. Kelly and team said. This is how we make an amyloid fibril. So right now the only FDA-approved therapy we have for our heart failure patients specifically is the TTR stabilizer called Tifamidus. But recently, if any of you attended ESC this past autumn, the results of the Acoramidus trial came, and they just was published in New England Journal a couple weeks ago. But right now the cornerstone of our therapy is Tifamidus. So we're gonna spend a few minutes shortly talking about that. Other things that we really wanna think about are sort of this holy grail. At the very end of this pathway, we can see the elimination of the deposits. Prior to the advent of silencers and stabilizers, how many of you were prescribing Doxy and Tudka? Couple of you, I will tell you I was, but am I doing that anymore? No, and these meds in order to be in the trial were excluded. So I really think those are a time of the past, and if you're still prescribing them, perhaps think about removing them from your arsenal. But other things that are really exciting that are currently in phase two and soon to be phase three trial are these monoclonal antibodies. Right now the phase two clinical trial is ongoing for the former drug by Pothrina called PRX-004. This is now taken over by Novo Nordus. And then the deplete TTR trial with Elexion and other monoclonal antibody is about to get started for a phase three where we can really go in and actually attack those amyloid fibrils and remove them. So more to come there. With regard to stabilizers, again, this is preventing that critical unfolding steps to ultimately increase the formation of that stable TTR tetramer and overall prevent or slow the progression of TTR deposition. It won't stop it. It won't reverse it. The key is slow the progression. So where did this come from in terms of Tefaminis? Tefaminis was launched as a sort of, I would say a tour de force of the colleagues in ATTR Act that was spearheaded by Dr. Maurer and the late great Dr. Rapetsi. And ultimately this trial looked at about 400 patients living with TTR amyloidosis. The average age of the individual in this trial was in the early 70s. Majority were men. Majority were wild type, about 25% were TTR. But what you can see here is that overall those individuals receiving stabilizer did better than placebo. By overall reducing mortality, but you can see this did not happen overnight. Time to reduce mortality. You can see the separation of the curves about a year and a half or 18 months. But we did see an overall 30% reduction in all cause mortality. Needed about seven to eight patients to treat to prevent one death at two and a half years. And four to present a hospitalization at one year. So time to treatment matters. Think about it. This is why we should be asking the question, why is my patient in heart failure? Maybe they have TTR. We have possible interventions. Because not only can we reduce all cause mortality, but people can feel better. They can walk better. We see a significant improvement in terms of six-minute walk decline. Meaning those individuals receiving Tefaminase, it wasn't like they were walking better or further. But those that were not on drug had a significant decline in their overall ability to walk compared to baseline at six months. You see the separation of curve. We also noted those people receiving drug like Tefaminase compared to placebo overall felt better. And once again, the separation of the curves was about six months. At the end of the day, why are we all caring for patients? We wanna make them feel better and potentially make them live longer. But it's not just about living. It's about feeling better in living. We look at the long-term extension data of the ATTR trial. So now about five years out, this was presented at ISA a couple years ago by my colleague and partner, Dr. Grogan. And you can see it about 30 months when individuals who are on the placebo crossed over. So these are people not receiving stabilized drug. When they crossed over, their rate of decline in quality of life seemed to have stabilized. Were those on treatment from the very beginning and then long-term, it's almost like their quality of life stabilized. It kind of, you don't have that same decline in quality of life. So there is something going on and they think time will tell. Unfortunately, I have no one test or sort of assessment tool to say the drug works. How do we know the drug works? The patients are showing us they're doing better compared to those not. And what about dosing? We know from the long-term extension trial that dosing also matters. This was looked at in the ATTR trial from the very beginning. You can see that in terms of thinking about not only dosing, but how bad is my heart failure? If you're starting patients who have less degree of heart failure, meaning those that are class one or class two, ultimately those patients will do better than those with more advanced like class three, class four were excluded from this trial. And once again, dosing does matter, but regardless of the dose, people do do better. And this is what I was alluding to my apologies in terms of long-term extension trial, up to 60 months or 50 months, we were really looking to see does dose matter and ultimately dose does matter. So more in this case is more. So when thinking about TTR therapies and now knowing we have options, how do you, each of you in this room, decide how you choose the therapy? Is it based on organ involvement, frequency of administration, drug safety, drug cost, mode of delivery, combination of factors? So think about how you would answer this question. Personally, I think it's a combination of factors. And this is kind of a next step of how you can think about that. This is a chart I modified from the AHA statement. Obviously since 2020, some of the drugs for TTR amyloid have been added. But I just wanna show you, we have deflunazol, which is a TTR stabilizer initially looked at in our hereditary polyneuropathy patients. I think there's some sort of single center retrospective reviews also that have looked at it in cardiovascular patients, particularly some work out of our colleagues at Columbia and Boston. But deflunazol is a TTR stabilizer, less attractive for our heart failure patients and certainly off-label because it has some NSA-like properties. So you do wanna think about renal function and bleeding, but it's cheap, it's about $180. A year when I was looking at some data, but certainly off-label. To FAMDIS is our first and only approved TTR stabilizer for cardiomyopathy. The nice thing about it is it's once a day, it's oral. There's nothing you really have to monitor for the most part. It is expensive, about a quarter million dollars a year. So you have to think about how you can get good costs for your patients, specifically with some patient assistance programs. And then we have our four approved FDA silencers. So we have Patizoran, Inotirzin, Vutizoran, and Planetirzin. These are the four silencers approved for hereditary polyneuropathy. And you can see here in the interest of time, but administration is different, monitoring is different. From a cost standpoint, they're all anywhere from four to probably $500,000 a year. So once again, looking at patient assistance programs, working with your industry for co-pay programs, something we need to think about, but ultimately maybe we as a society need to do more in terms of lobbying to bring down costs for our patients. So getting back to that gentleman I mentioned, I met him in 2017. Remember, TTR therapies did not hit the scene until 2018, but maybe we could have thought about trial. In 2018, drug was available and he was initiated on Patizoran, the first approved silencer. From 2017 to 2021, he overall was doing okay. In fact, his functional ability approved. And then he had some hematuria, so we proceeded with arenal biopsy. There was concern from malignancy and ultimately he hadn't affected me, but in fact, all he had was amyloid in that kidney, oodles of it. And currently he continues to be my heart failure patient. So hopefully what I wanted to show you by this is this is a gentleman who I've known for about five years. Remember, thinking about him in heart failure with very advanced TTR amyloidosis, he should not be here anymore, right? So I do believe that these disease targeted therapies are changing the natural course. And if you remember anything from today, if you wanna take a snapshot of the slide, I too modified it from Dr. Ruberg and colleagues in the Boston program. But right now, this is our current arsenal that's available for us, those with wild type cardiomyopathy. And then for hereditary patients, these are things that we can think about. Antiplasma cell, all right? So these are our patients who are living with primary ale amyloidosis, whether it's Kappa light chain or Lambda light chain. So this is the case. This is a young woman that myself and a colleague in the room met actually several years ago who came to us for a third opinion. She had already had multiple pericardiocentesis. She even had a window done for pericardial fusion of unclear etiology. She came to me with very bad heart failure, Mayo stage four. I directly admitted her to the hospital to expedite her care. And why do we worry about this? Because ale amyloidosis is a hematologic emergency. This is the equivalent of your sort of ST elevation MI. We do not wait for the light chains to destroy the rest of the body, just like we don't wait for lack of blood flow. You're going to go get help. At the end of the day, a Mayo stage four, which is highlighted by this sort of orange curve here, 50% survival at six months. 30% of these patients living with ale amyloidosis will die within one year. So just so you know, sort of our arsenal really has been changing, particularly since the mid 2000s, around 2012 or so, sort of the cornerstone of therapy with Cyborg D. But as a couple of years ago, Dr. Kastridis and the Andromeda trial really revolutionized the field, as we're thinking not only about Cyborg D, but Cyborg D with Daritunamab. And that came from that paper I listed down here. Kastridis and Andromeda, for those of you who are interested. This was a randomized control trial comparing standard of care Cyborg D with Cyborg D and Daritunamab, looking at about 400 patients. And overall, those patients receiving the new agent, Daritunamab, combined with classic, had a 50% chance of complete remission within a few months compared to the control group with an odds ratio of 5.1. So really a game changer for those individuals. But it's not to minimize that this is not of a nine thing. And even with therapies, these patients are still dying with cardiovascular complications despite getting into hematologic remission. So they really do need your care and attention. So this young lady with Cyborg D back in 2020, within two months, she actually went into complete remission. I saw her a few months ago. Thankfully, she remains in complete remission. She was a young woman who was on 200 milligrams of torsemide for those of you not familiar. That's a high dose. She now just takes it as needed. So her heart failure has really changed. And she's back to carrying a purse, Dr. Larson. And she walked in our clinic, couldn't even carry her handbag. So it's really, it's really nice. But what about therapies? If stabilizers and silencers aren't working, we have a few more tools in our toolbox. Please don't say just because you have AL amyloid, we just have to send you to palliative care and hospice. Think about referring to someone like myself or other colleagues who really can offer those extra tools or at least have the conversation saying, I'm sorry, you're not a candidate, but here's what I'm gonna help you with. And that includes heart transplantation. Back in the day, people didn't think heart transplantation was an option for our patients. And ultimately, however, when we reviewed modern data from UNOS, we saw that there was no difference. That is our United Network of Organ Sharing. Most recently, we looked at our own male enterprise data where we had about 60 patients with amyloid cardiomyopathy compared to 1,400 non-amyloid patients. This is across our enterprise. Once again, no difference. This is 10 year data with median follow-up of just over eight years. So really exciting. And at the end of the day, this is why we do this. So this patient I just saw two months ago for his third annual heart transplant follow-up. Here's him with his grandchildren at five weeks old. These grandkids are now five years old. He's three years post-heart transplant and has a lot of life to give. So lastly, what's next? There are a lot of clinical trials in the pipeline. Right now, cardiotransform and HEOs are really gonna hopefully help us answer the question, could we do combination? Should we be thinking about it? Is it responsible from a financial standpoint? But these are looking at silencers already approved for hereditary polyneuropathy, but now we're looking at them in cardiac patients. As I mentioned, a tribute was a trial that was recently published in New England Journal. Presumably this will be the next TTR stabilizer on the market. Magnitude is coming. This is looking at, it will be a phase three RCT, looking at the CRISPR-Cas9 therapy in our cardiomyopathy patients. It will include both hereditary and wild types, so very exciting. Here are some clinical trials for those of you interested in primary amyloidosis. These are looking at the most advanced heart failure patients looking at a monoclonal antibody in our primary amyloidosis patients. Just wanted to show you a quick picture. This is looking at that TTR stabler acromidus, which is a super stabilizer. It mimics 3-1-19 methionine, which is a super stabilizer. It's shown to stabilize more than 90% of the tetramer to prevent that formation of the amyloid fibril. And just to kind of show you a minute, it met its primary endpoint of overall reducing heart failure hospitalizations and all-cause mortality. So with that, I leave you with the following. Tefamidus is the only approved treatment for individuals living with TTR cardiomyopathy that showed a benefit from a morbidity and a mortality standpoint. Time matters, so think about it, whether it's for primary amyloidosis or TTR, I only really showed you TTR data, but really time does matter. Think about advanced therapies if you're struggling with a patient, refer them. Lastly, what I wanna say is hope is here for our patients and this is just the beginning. I could not do this without my team. And with that, thank you. Thank you. Thank you.