 It's my pleasure to introduce Dr. Julie Rosenthal, who's going to be speaking to us about emerging therapies and potential obstacles, including on navigating prior authorizations. I just say parenthetically, there are two great things about amyloid as a field. One is the patients are lovely, and two is get to watch colleagues like Dr. Rosenthal develop really amazing programs all by herself with the help of other colleagues. And she's become one of the national experts in this arena. So pleasure. Thank you, Matt. And thank you, everyone, for allowing me the privilege to be here with you today. It's truly an honor to be at our inaugural ASU cardiac amyloid osis symposium today. Over the next 20 minutes, I hope to provide you a tour de force of therapies for both TTR and AL amyloid. These are my disclosures. Hopefully what you will appreciate by the end of this morning is that there's truly been an explosion in the development of therapies for individuals living with amyloid osis. We have multiple strategies, and no longer do these include only palliative and pastoral care. But we actually have therapies that will reduce overall morbidity and mortality for our patients living with amyloid. So how did we get here? It was almost 150 years ago that Dr. Virkel first described this starchy protein, what called amyloid. But only 30 years ago, did we actually have our first intervention for hereditary polyneuropathy amyloid osis patients, specifically with liver transplant. And then it was almost 30 years ago that our colleague, Dr. Kelly, at Scripps really described the kinetics that led to understanding how amyloid fibrils of TTR background form, which then launched the work into Tephamnus, which ultimately led to the approval of our first stabilizer in 2019. But silencer therapies hit the market in 2018. And we now have three silencer therapies available for our hereditary polyneuropathy patients. And most recently, approximately a year ago, or two years this month, we had the FDA approval for our very first AL amyloid drug, daratunamab. Everything else prior to that had been used off label for AL amyloid. So this is an overview of this morning. We're going to start with highlighting some therapies for TTR amyloid osis. Knowing this is a cardiac symposium, I really just focus our attention today on Tephamnus. But I want to highlight there are several other therapies available. Then we'll talk about some plasma cell therapy and some other therapies for advanced patients. So to set the stage, I'd like to begin with a case. We begin with a patient I share with Dr. Goodman. He's a 65-year-old gentleman with hereditary TTR amyloid, 380-ALA. And he, like most 380-ALAs, had a mixed phenotype, including both cardiac and neuropathic phenomenon. He was quite advanced when I met him several years ago. And his advanced stage was defined by his cardiac involvement, as this is the driver of morbidity, mortality, and patients living with amyloid. You can see that by his elevated cardiac biomarkers. We saw earlier from our colleague Dr. Burke some classic features of individuals with amyloid on ECHO. So this is a Mayo apical four. Hopefully, you can all appreciate the bi-ventricular thickening here in both the LV and the RV, as well as some bi-atrial enlargement and inter-atrial septal thickening. And on the right, you see the classic apical sparing strain pattern, otherwise known as the cherry on top. Here is his Technizium pyrophosphate scan. You can see here that the tracer lights up greater than or equal to the bone, so he was a spectra grade 3, consistent with his diagnosis of TTR amyloid. So in this setting, what would you do? How many of you would start him on a silencer, stabilizer, maybe enroll in a clinical trial, start combo therapy, revert advanced therapies? How many of you have no idea what I'm talking about? Well, hopefully by the end of the morning, you'll feel a little more comfortable. Again, I want to set the stage really on stabilizers. You've already seen this diagram already this morning in different iterations, but I just want to highlight the formation of TTR amyloid. Again, it all begins in the liver. The liver makes this tetrameric protein called TTR, or transthyretin. It's this critical unfolding step of that tetramer that leads the development of amyloid fibrils, which then ultimately deposit anywhere from head to toe, leading to a multi-system dysfunction. So we have three main pathways to prevent and delay the progression of individuals living with TTR amyloidosis. We can start at the liver with silencer therapies. Again, these include patiziran, anotiracin, butiziran. We can actually target this circulating TTR tetramer itself with stabilizer therapy. We'll focus today on tephamidus, and perhaps the holy grail will come with actually extraction or removal of fibrils. This is otherwise known as degrater. There's a lot of work going on right now in the monoclonal antibody arena, both for TTR and NAL amyloid. But again, I want to highlight tephamidus today as this is our only approved therapy for individuals living with cardiomyopathy and TTR amyloidosis. Again, a stabilizer there is to prevent that critical unfolding step. So we lead to an increased concentration of serum TTR, and subsequently a decrease in deposition. For those of you not familiar with tephamidus, it really made this stage a couple of years ago thanks to our champions of amyloid, Dr. Maurer, who's here today, and Dr. Epizzi, who our community recently lost, do their work and colleagues for the ATTR Act study. This was a randomized control trial looking at different doses of tephamidus, a high dose, low dose, and comparing to placebo. And overall, we saw a significant reduction in mortality. You can see separation of curves here at about a year and a half in individuals taking tephamidus compared to those not. We saw overall 30% reduction in all-cause mortality. The number needed to treat prevent one death at two and a half years is about seven and a half patients, and four patients prevent hospitalization at one year. Not only does this stabilizer demonstrate a reduction in mortality, but we saw a reduction to overall morbidity. You can see there's a significant separation of curves at six months in terms of the decline of a six-minute walk. So individuals on tephamidus seem to walk longer and stronger at around six months and over time compared to those not on stabilizer. Not only do you see improved morbidity from a functional standpoint, but also quality of life. Most of the people in the room are familiar with KCCQ. You can see that the decline in KCCQ scores is less steep than the decline in individuals not receiving drug. We once again saw significant improvement at about six months. This was recently presented at ISA by my colleague, Dr. Martha Grogan, looking at the long-term extension data from the ATT-R trial. On the top, you can see individuals who are initiated on tephamidus from the very beginning. This is the yellow line. As you can see, the gray is the placebo, but at 30 months, individuals in the trial were allowed to cross over and ultimately allowed to receive stabilizer therapy. And hopefully what you can see on the gray curve is that the rate of decline in the individuals who were once on placebo and converted to drug has slowed down. And then the decline in the individuals on tephamidus doesn't really seem to be declining anymore. It's almost like they've reached a steady state now over a five-year follow-up. Once again, highlighting that their quality of life continues to be better. In addition to reduction in morbidity and mortality, we've heard already from my colleagues this morning that timing does matter. We know that trying to pick up people earlier in disease tend to have better outcomes in terms of morbidity as well as mortality with hospitalizations and survival. So individuals who are started on treatment later in their stage of amyloid tend to do less well compared to individuals who start earlier in their journey. Also, we know that regardless of dose, individuals receiving some form of tephamidus do better than those not receiving tephamidus at all. But does dose matter? More recently, our colleagues published that, yes, dose does matter. You can see here on the forest plot that dose mattered not only in the initial trial, but also in the long-term extension trial. Those receiving higher dose tephamidus, 80 milligrams compared to low dose tephamidus at 20, did better. So knowing that we do have multiple therapies, how do we choose a specific therapy for individual living with TTR amyloid? Is it based on the organ, based on how the drug is administered, the cost of the drug, or is it a combination of factors? Obviously, this morning, I did not go through all the drugs. But as I highlighted, hopefully, for you in that timeline, we now have four approved drugs by the FDA for amyloid. But this table that was adopted from Dr. Kittleson and colleagues highlights that we have three FDA-approved silencers, specifically for hereditary polyneuropathy patients. We have one stabilizer approved for our cardiomyopathy patients, both hereditary and wild-type. That is tephamidus. And then we have deflunazole, which I think some of us in the community continue to use off-label really because of cost. As you can see on the far right-hand side here, the cost of these drugs is extraordinary, as Dr. Post alluded to. And while there are financial assistance programs available for our patients, I think we, as a community, need to do better and need to do more. So getting back to our case of this gentleman I met, we initially met in 2017. And remember, in 2017, aside from liver transplant for hereditary polyneuropathy patients, there really wasn't any therapies around. In 2018, he was initiated on the first drug available, which was a silencer, patizoran. And over the course of those four years, he actually did much better. He got off of walking with a walker. His heart failure improved. Clinically, he was doing much better. Interestingly, in 2021, he develops an intermittent hematuria. For this, he underwent a renal biopsy that raised question of malignancy. And ultimately, he underwent an nephrectomy. And all the nephrectomy showed was oodles and oodles of amyloid. So I think that there's still a lot to learn about how TTR proteins can affect the kidney. This gentleman did not have any proteinuria. And currently, he continues to be with us, but is living with some progressive heart failure. The importance of this case I want to highlight, I believe it was Dr. Vijay, who talked to us this morning, median survival for an individual with hereditary TTR amyloid used to be about two and a half years, three and a half for wild type. But currently, with the advent of all of these therapies, we're changing the natural course for these patients and their families. So this is a nice summary adopted from Dr. Ruberg and colleague, really just to highlight that we do have options for our patients. This doesn't even highlight what's to come. Apollo B was recently presented at ISA and HFSA, and I believe is in progress with the FDA. So potentially, Patiziran might be available for our wild type cardiomyopathy patients, but for now it's to Feminis, as well as off-labeled Diffusinol. Again, for hereditary patients, specifically those with mixed phenotype, I think we should consider silencer versus stabilizer. The data has yet to really be presented. You know, should we do combination therapy? Is silencer superior to stabilizer or vice versa? I think more to come on that front. So switching gears to AL, amyloidosis and anti-plasma cell therapy. I'd like to just start with another case. And I think this case highlights a few stereotypes. One, amyloid is not just a disease for men. This is a young woman of Jamaican descent who presented for her third opinion re-heart failure and was actually found to have light chain amyloidosis. She presented in quite an advanced case, she was stage four with clearly symptoms of failure to thrive. She had actually undergone a pericardial window to recurrent pericardial effusions more than a year prior to meeting me. She was having recurrent pleural effusions, necessitating multiple thoracentesis. You heard earlier from my colleague a little bit about Mayo staging and whether you use Mayo staging for TTR amyloid or AL amyloid, once again, it's the cardiovascular pathology that really highlights the morbidity of these patients. So here is that AL staging curve again. And I think one of the thing that I would just highlight in addition is these curves remain quite steep. Overall mortality for an individual with stage four amyloid untreated is less than 50%. And that's highlighted by the sort of brown curve there. Thank you. But these curves like I tried to show you with the TTR case are really changing. Most of this data stems from old treatments, old chemotherapy-based treatments for individuals with AL amyloid, such as the Melphalan prednisone therapies that most of us when we were in training were most exposed to. Cyborg D really didn't hit the scene until 2012. But now we have a lot of things in our arsenal and I apologize, this is supposed to be not there. But basically we have a lot of different agents whether it's Melphalan or prednisone, but Cyborg D has really been the standard of care up until more recently with the Andromenotile leading to Cyborg D-derotunamab. This has truly been a game changer and I think more things to come with novel therapies and perhaps targeting cytogenetics to tailor therapy for our patients. But Andromen I just wanna highlight, this was published just over two years ago and now that led to a game changer for our patients living with AL amyloidosis. Derotunamab is a monoclonal antibody targeting the plasma cells. And what this trial looked at was a randomized control trial comparing our control group which was standard of care Cyborg D, cyclophosphamide, vortizumab, dexamethasone versus the Cyborg D plus derotunamab. What hopefully you can see is that there is a significant risk reduction in individuals with the Cyborg D-dera compared to the control group. More than 50% of these patients were able to achieve complete remission compared to just under 20 receiving our prior standard of care Cyborg D. So getting back to our young lady, she actually started Cyborg D-dera prior to the FDA approval. We were using off-labeled D-dera back in this time period in August of 2020. It took her two months to normalize her free-lighting ratio and at that time she was actually in complete remission. This was actually shown in Andromeda which she would have been excluded from because she was in Mayo stage four. So they excluded the sickest of the sick patients. This demonstrates that you can use this regimen in quite sick patients. And I recently saw this young woman last month and thankfully she remains in complete remission. She is now on surveillance monitoring. And just to highlight how much remodeling can change, I think you saw a nice example from Dr. Goodman when you're thinking about remodeling from an autonomic reflux study and so forth. We definitely can see some cardiac remodeling. This young lady was requiring 200 milligrams of torsumide daily with intermittent boosters to control her volume status. She was initially getting multiple thoracinthesis. Now she has not had a recurrent pleural effusion in almost two years. And when I saw her in clinic last few weeks ago, I decreased her torsumide to as needed only. She is back to living life. But what about patients who are really this advanced patient who I think have missed the boat when it comes to potential turnaround with chemotherapy or stabilizer or silencers? We can think about transplant. Otologous stem cell transplant is still used for certain individuals living with AL amylidosis but I think our program is steering more and more away because we are finding that therapies are working for our patients. Knowing that I'm a cardiologist and this is a cardiac amyloid symposium, I just wanna highlight the role of heart transplantation and I'll save stem cell transplant for another time. But people back in the day used to think that we could not transplant our individuals living with amyloid. And this comes from old data out of Mayo Clinic actually showing that individuals with amyloid tended to do worse. A more modern cohort looking at our United Network of Organ Sharing Data from 2008 to 2013 demonstrated in fact that individuals with amyloid can have just as good outcomes as individuals not with amyloid. The difficulty with UNOS data reporting system is it doesn't differentiate between those with AL amyloid which you have seen perhaps have a greater morbidity mortality compared to those with TTR amyloid in some respect. And so it's kind of among us as amyloid centers of excellence to kind of look at the data a little bit more granularly. Our colleagues at Columbia as well as other centers like Stanford and Cedars have demonstrated while numbers are small that these patients whether they have AL amyloid or TTR amyloid can have just as good outcomes as those not living with amyloid. And I think this stems from us understanding as a community who these patients are, what their comorbidities are and making sure patient selection prior to transplant is good. And I think what's really interesting now these cohorts that I'm highlighting here this is prior to the era of actual stabilizer therapy or silencer therapy. So I think there's going to be a lot more to come in the future in terms of how we're managing them. And just to show you that, you know, since we've all been in the room kind of looking at data points and graphs these are the people we're talking about. These are the people who hopefully we're impacting their lives as well as their family's lives. I actually just saw this gentleman for his four year annual follow-up he just finished a 5K back in North Dakota. This was actually a patient sent to me from Dr. Grogan. So this was his one year heart transplant anniversary but now he's still out there living life. And next to him is Kathy. Kathy we met after basically one cycle of chemotherapy with Cyborg Didera on a balloon pump. And ultimately we transplanted her and she is going to have her two year anniversary this March. She is actually only on surveillance. She is not required to stem cell transplant or recurrent chemotherapy. And I think that's a question that myself and colleagues are charging our hematology colleagues. You know how much, how long do we need to continue these people on therapy versus just maintenance. So with that, what's to come? You've already heard from my colleagues, Dr. Post, Sonya Sobrowski and others. There are so many clinical trials available. I would encourage you to go to clinicaltrials.gov today. Last night I typed in two keywords treatment and amyloid and more than 500 hits came up alone. Cardio transform for any of you in the community who are still in role who are still caring for patients. This clinical trial is still enrolling. Helios B hopefully will have data come out in a couple more years. This is looking at Vutisaran silencer therapy. It's an in depot injection. Acoramides waiting for the results hopefully the next year or two, maybe sooner, two years. No, no, no. June. June. Okay, excellent. What about gene suppression therapy? This is really going to be, potentially it'd be a game changer. You perhaps have seen a couple years ago with New England Journal published a case in our hereditary pulneropathy patients. Seven patients showing one dose wonder that can really change your entire genetic makeup. Phase two clinical trials are ongoing and phase three are in the works. But this really could be a game changer for not only our patients living with T-terameloid but perhaps other diseases. And then a lot of monoclonal antibody trials are going on right now. These are two active trials for individuals with AL amyloid. And what's nice about these trials is they're including our really sick cardiac patients. Affirmal is looking at these Mayo stage four patients who otherwise would have been excluded from clinical trial. Kale 101 is looking at a different staging system but again, sick or heart patients with Mayo stage three A and three B. So I think lots to come and encourage you. And with that, I will just close with this image by Monet. This was the actual painting that launched the movement of Impressionism for any Impressionist lovers in the audience. This is called Soleil Levant or the Sunrise. Really, I just think amyloid-targeted therapeutics, they're finally here, but there's a lot more to come. And I think tailored therapy is certainly on the horizon with gene suppression, maybe looking at cytogenetics and thinking about those who might respond to venetoclax if they're not responding to the cyborg edera and other things. So with that, I could not be here without my amazing team. So I wanna thank them as well as all of you for being here. Thank you.