Mayo Clinic cardiologists Martha Grogan, M.D., Melissa A. Lyle, M.D., and Julie L. Rosenthal, M.D., focus on new transthyretin amyloidosis (ATTR) therapies in this video first shown on
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Mayo Clinic Medical Professionals — Cardiovascular Diseases. Yeah. Yeah. Hello and welcome back to the Mayo Clinic Medscape cardiology video series. I'm Martha Grogan. I'm the director of the cardiac amyloid clinic at Mayo Clinic in Rochester Minnesota. And today I'm really thrilled to have my colleagues with me Dr julie Rosenthal who's the director of the cardiac amyloid program at Mayo Clinic in Arizona and dr melissa lyle, who's the cardiac amyloid lead for the multidisciplinary amyloid clinic at Mayo Clinic florida. So welcome julie and melissa. We're going to focus on the new transparent in amyloid therapies today. But I'm just going to briefly mention that cardiologists should know that a L treatment is really improving. Especially with the use of derek tumor map. So this is really a game changer and all types of amyloid. We're now seeing improved outcomes. So we're gonna briefly talk a little bit about what is transpiring in amyloid and what are the drugs that we have to treat this condition. So, transparency is a protein that we all make. It's produced in the liver and it transports thyroid hormone and retinol binding protein throughout the body. So here one sees the structure of the T. T. R. Protein and just to remember that there are two main types of amyloid that can infiltrate the heart A. L. Which is due to a monoclonal disorder of the bone marrow and Transpire a tintype amyloid where the protein is produced in the liver and of the T Tr amyloid types. There is both wild type which is much more common in hereditary form. So just a quick overview of that and when we look at transpire it in again and transparent in amyloid, there's no actual disease of the liver. The problem is after the protein is formed. So the liver produces T. T. R. And it should stay intact. But in transparent in type amyloidosis, it breaks apart those monomers then kind of glom together and form amyloid that infiltrates the heart and the nerves and other organs and tissues in the body. So as we talk about these drugs, the reason I showed you that movie is we have a site of action being at the liver. We can have a stabilizer drugs that happen at the level of the actual protein and we can talk about fiber disruptors or dig graders and here I've kind of listed some of the names of the medications and whether or not they're in clinical trials or whether they're approved for use. And so now we're going to go on and just kind of talk a little bit about these therapeutic. So I'm gonna start with melissa. Could you um talk to us a little bit about the TT our stabilizers? Sure, absolutely. So the first one that I kind of want to mention is to feminist. So to feminist, is that once a day oral medication that really stabilizes the T tR te trimmer by binding to the T. Four binding site. And actually this was the first therapy for a T Tr cardiac amyloidosis that was approved by the FDA Back in May of 2019 and that was really after the attract trial. So the attract trial was a randomized double blinded study that enrolled 441 patients to either 80 or 20 mg of two feminist or placebo. And the trial demonstrated a 30% reduction in all cause mortality with two feminist compared with placebo as well as a 32% reduction in cardiovascular hospitalizations in patients that were new york heart association class one or two. So some of the secondary endpoints from that trial really demonstrated a reduction in the decline in the six minute walk and also a lower rate in the decline of quality of life that was assessed by the Kansas city cardiomyopathy questionnaire. Further subsequent analysis that showed that there was actually a further reduction in all cause mortality with the 80 mg dose, which is why that's the preferred dose. So, to feminist is really are FDA approved therapy for a T. Tr cardiac amyloidosis. Great. And you know, a question that comes up all the time is um once a patient is on to feminist, how do we follow them any guidelines for our audience in that regard? Yes. So that's a great question. And really there's no great way currently. So the drug how it works. Is it slows the progression of disease? It doesn't necessarily reverse the disease. And so if there is any sort of clinically relevant regression that would take years to decades to show. So the ways that we follow patients are mostly by clinical assessment, so continue to follow them clinically by physical exam and their general heart failure symptoms. We also have found that frequent serial echo imaging is not that useful either. Follow up echoes can be useful if there's been progression of symptoms and we think that the echo might change our management or if they're getting cereal echoes for another reason, for example, can common in aortic stenosis. But otherwise we're actually not getting frequent serial imaging as well. Serum T. TR levels are an indirect measure of stabilization. So it's very reasonable to get a serum T. TR level at baseline. And then also once after therapy has been started. But really the utility of serial serum T. TR levels is yet to be determined because currently there's no role for a change in dose or up filtration of medication but that might potentially play a role as a biomarker in the future. But right now it's mostly following the patient clinically. That's great. And um again, we know that there's really no need for safety monitoring. Sometimes people think there are safety labs that we need, but this is a very well tolerated drug and I might briefly mention that typhoon assault is also an excellent stabilizer. Um It's not studied in a randomized uh trial for cardiomyopathy specifically. But for patients who have adequate renal function. Sometimes we need to use the iphone, it's all because of the financial toxicity of two families. And how about anything else on the horizon? Um For stabilizers? Yes. So and that's a great point about the diploma soul to we just caution about monitoring renal function as well as worsening heart failure symptoms. But in terms of other potential options in the future. So A G 10 is another stabilizer and it actually mimics the stabilizing capabilities of the TT R variant T. 1 39 M. This is a variant that's been shown in the past to actually be protective against development of poly neuropathy and patients that are hetero zegas for the V. 50 M mutation. So this is another stabilizer with phase two. Studies that have shown some degree of increase in serum T. TR levels as well as stabilization of the T. Tr te trimmer And Phase three studies are currently ongoing. So hopefully we'll have new information soon about additional stabilizers. Great thanks so much. So that was at the level of the protein and julie. How about if we go back a step to the liver? Tell us about the silence or therapies uh that we now have available for T. Tr amyloid. Good morning Martha and thank you. Yes. We currently have to silence our therapies approved specifically for individuals living with hereditary amyloidosis. The pulling a rope, a thief genotype. These two silencers will have different mechanisms ultimately have the same goal and that goal is by preventing translation of that teach er protein so that as we overhaul of a decrease in the serum concentration of trans sky written. And as I mentioned they are mechanistic lee a little bit different. So the first type of silencer we have is called Patisserie. In this was first approved back in 2018. Specifically in hereditary patients with poly neuropathy. And in the clinical trial, Apollo demonstrated an overall improvement in these patients poly neuropathy score which is four parts of nature. Looking at autonomic dysfunction sensory loss, um strength as well as re flexibility and it showed improvement over time suggested that the silence are not only halts the progression of amyloidosis but there's perhaps a potential for regression. We also saw in this clinical trial and improvement in overall quality of life in these patients receiving silence or therapy. Petit's around specifically is an infusion medication that is received every three weeks by these patients. Just like we heard with our stabilizer therapies. These are lifelong therapy specifically the silence our meaning they're not there to um completely erase the disease. They're there to sort of slow or delay the progression of disease. But it is going to require lifelong therapy in order to receive the infusion. The patients do require pre medication therapies specifically with steroids as well as an anti parasitic and anti histamine. So that means every three months they will be receiving decks a method zone to prevent any sort of infusion reaction. In addition to Petty's Iran we have another silencer called I know Tillerson I know Tillerson like Patisserie and halts the progression of R. T. TR protein formation. Like the Apollo B. Trial. We had neuro T. Tr. And narrow T. TR. Specifically looked at patients with hereditary poly neuropathy. And like in the Apollo B trial we also saw an improvement in their overall neuropathy function as well as quality of life. Similar to Patisserie in this too will be a lifelong therapy. But the administration of I noticed sauron is something patients can do in the comfort of their own home by providing themselves with the sub Q. Injection once a week. However this medication is a little bit different and it does require specific monitoring. As we did see some safety signals particular with regard to thrombosis. Dapena as well as glow marina friday. So renal function as well as platelet counts do need to be followed. Great. And you might just tell the audience what happens to the serum T. TR levels on the silence or therapy. Excellent question. So unlike stabilizers where we see an increase in our transparent and concentration and if you're looking in your own labs that would be mimicked as your pre albumin levels in individuals with silence or since we're preventing formation of transparent and you'll see an overall decrease in your pre albumin levels. Great I think that's a really important clinical point and then for the audience to know. So again these silencers right now are only approved for hereditary patients with neuropathy. They can have cardiac involvement but not just isolated cardiac involvement. And then there are what I call the next generation of both of these drugs um that are easier to administer subcutaneous. Um Sometimes once even once a month or every three months. Maybe even less than that. So there's a lot going on with cardiac trials now both with these agents but also with the next generation. So we're really going to have some exciting data coming in the future of how to use these for our patients with amyloid cardiomyopathy and melissa. Maybe can you tell us what's going on as far as disrupting the fiber rolls? Yes so there are several emerging agents for disruption or degradation and really to Phase One studies. So pr X 004 is an intravenous monoclonal antibody. This is actually administered via an I. V. Infusion every 28 days and it clears amyloid deposits by binding to the misfolded T. Tr another form is in 1006 which is a recombinant I. G. G. One human monoclonal antibody. This really is aimed at targeting and the misfolded and aggregated form of T Tr. So of course just Phase One studies currently. But lots of new things on the new and exciting things on the horizon for degradation and disruption of those amyloid vibe roles and that's always something that patients ask about. I will comment that there's been a lot of interest in this type of therapy um including an A. L. Amyloidosis. And there will be probably some newer trials going on but it's not an easy thing anyway and I've always wondered once if you actively degrade the fibrosis what will be left behind? But we have a lot to learn in this area. Sometimes you um some providers might see patients that are on the combination of doxycycline and tugged ca which was promoted based on some animal studies as far as being a firewall disruptor. So you might still see patients on that if they're doing really well. Sometimes we continued them but we're not usually initiating patients on that uh therapy at this time. Um and then julie back to the liver, you're the liver expert. Tell us you've heard a lot in the news about CRISPR therapy particularly for T Tr amyloid. Yes, CRISPR CAS nine intervention is a gene suppression therapy that made headlines this past june in the new England Journal of Medicine specifically looking at only six patients with hereditary pulling our apathy. This was a phase one clinical trial and I think it's far from prime time but certainly exciting and with the use of CRISPR therapy, what we saw we could do is um induce the cells natural repair process to overall delete that T. T. R mutation and suddenly knocked down all T TR formation. And so the question is will this actually work um and clinically have benefits. So I think there's more to come but certainly exciting particularly think about our other current therapies that are requiring either daily administration or weekly or every few weeks. The idea of this is it's just a one time infusion. So certainly more to come. It's just it's really amazing when we went from almost no treatment for this disease. Well nothing for wild type T Tr other than organ transplant. Um And liver transplant was our only real therapy for hereditary Emily to all of these potential therapies. So it's just an explosion in a good way and I want to highlight for the audience. I mean sometimes the most important thing we can do for our patients is to give them resources where to get more education and also how to stay informed about clinical trials. So I've just listed for you, we actually have a male clinic amyloid Youtube channel, believe it or not. Um There are a lot of excellent patient support groups and patient advocacy groups including the Al Amyloidosis Foundation Amyloidosis Research Consortium and the amyloidosis Support group also for faculty members. Not listed here, but there is a group that it really helps bring education to medical students. So I can help you with your faculty if you need to make sure that medical students are learning about amyloid, which of course the three of us think that there's a need for more education And then I just highlight all the different things that are on our Youtube channel, which includes a genetic counselor. Uh of course, that's not a substitute for genetic counselor in person. But some really important information for our patients on those Youtube videos that are available. And then just to highlight that enamel it in general. But even especially in cardiac gambling, we have a big group of individuals from all of the various sites Rochester Arizona and florida who you really are specialists in seeing and treating these patients. So it's really been our pleasure to share this information with you. Thank you so much to julie and melissa and thank you to our audience for joining us on the heart dot org. Medscape Cardiology. Yeah, yeah.