Advanced heart failure cardiologist and cardiac amyloid specialist Hansie Mathelier, MD, discusses AL Amyloidosis, the importance of diagnosis, and the current and potential future therapeutic options. She also touches on transthyretin (hereditary and wild-type) and the overlap in terms of diagnosis.
Twitter @PennMDForum Dr. Mathelier’s physician profile So I'd like to um introduce dr hans. Metalious, who is part of the cardio oncology program uh primarily at Presbyterian Hospital. She finished her training at residency training at Hopkins and then did her cardiology and advanced heart failure training at Penn and she's an advanced heart failure uh uh position at penn and Presbyterian Hospital but has a particular interest in amyloidosis and how that connects with cardio oncology. So, given all of the advances that are occurring in the field of vale amyloidosis, we had wanted her to give a talk today and and share some of the the directions of this field. So thank you so much. Good morning everyone. Can you guys see my screen from the PowerPoint. Okay, perfect. So I just wanted in terms of the overlap of discussion of ale amyloid and I'll also touch base also in terms of trains three written since a lot of us will see an overlap of these patients in terms of diagnosis. So I have no disclosures pursuant to this talk. So, just in terms of the importance of this disease, um there's always known that there was a misdiagnosis and delayed diagnosis from a recent study about a couple three years ago, it was noted that 75 of patients saw greater than three physicians prior to diagnosis was made. And for 63 of the patients, it took greater than six months to diagnosis. 44 of the patients received an incorrect diagnosis, 31 required air travel. Only 18 of those with Cardiac L. Had the correct diagnosis made by a cardiologist and then cardiologist were the most common subspecialty to make a misdiagnosis. And often they would be concomitant with hypertrophic cardiomyopathy. So when we talk about cardiac amyloidosis in particular, we talk about the three types of hallmarks. We talk about light chain amyloid, which is based on immunoglobulins. Um in terms of what can be involved as the heart, kidney and the peripheral nervous system. There's about 2500 cases per year with half of them having cardiac involvement. And then we talk about wild type transpire it in a late onset. It's an important cause of heart failure with preserved EF. Um And then we have the hereditary or variant at our which is a point mutation that is autism, a dominant with incomplete penetrates that can also involve the heart peripheral nervous system and the system. In terms of this is just a quick little summary in terms of putting these into buckets in terms of A. L. A. T. T. R. The average age of our male patients are going to be 55 for our mutant T. Tr 50. And then with the wild type of 75. Um There is a 50 50 split for our light chain and mutant T. T. R. And then for um wild type it's predominantly male. Um 95%. Um In terms of the cardiac involvement as you guys can see can be some studies have shown 30 to 50% for the mutant variable and then all and then for fat pad biopsy. If you're concerned about at our never let the fat pad biopsy stop you from diagnosis. It's predominantly positive in our ale population in terms of extra cardiac manifestations. In terms of L. We talk about necrotic on economic and purpura. And then for a tr we're talking about neuropathy, peripheral neuropathy um definitely in terms of the importance of diagnosis is in terms of treatment and the median survival patients with L. 12 to 36 months and then if they have heart failure 4 to 6 months and then for a. T. T. R. 70 to 75 months. So we're specifically starting off talking about l. We're looking at prognostic values in terms of the pro BMP. Troponin T. And um the light chains patients that carry the translocation left 11 14 have a worse prognosis. And when we talk about therapeutic strategies, we talk about uh produce um inhibitors, calculators, antibodies, steroids and mads. And then also we talk about stem cell transplant. The forefront in terms of patients with l. Amyloidosis is cyborg D. Um There was 230 patients with um in the initial study was looking at the front line with cyborg D. There was overall Hemet logic remission with 60%. The cardiac response was was reached in 17% in cardiac patients And 25 in real. And then patients with cardiac stage three showed an anti pro Bmp greater than 85 had a lower response rate and poorer survival hematite logic response improves survival in these patients. So, in terms of a game changer in this disease process has been dared to be met. This is a note to Queen's gambit, but in terms of data to be mad plus cyborg D. Trying to go for al amyloid. So, this was the drama to trial. That was published earlier this last year. In middle last year. And what this was was looking at sub Q decorative ahmad plus cyborg D. It was noted to be well tolerated in these patients. They did exclude Mayo Stage three B with those patients with newly diagnosed amyloid. And then there was a robust hematite logic and organ response in these patients, noting for the cardiac renal and then liver response. So, in terms of their youtube, a map has really been a game changer in this disease process. In terms of when we're talking about patients in terms of actually seeing a difference. In terms of saying can we have a good mainstay with chemotherapy? In terms of saying do these patients need to have stem cell transplant? Patients are still going undergoing stem cell transplant but that population has definitely gone down over the past couple of years. In terms of what's in the horizon. There's um currently of um futures for phase three trial. It's C. A. 101 It's an anti anti amyloid antibody. It's Acai Merrick monoclonal IgG antibody that targets the human vengeance jones protein where they're stronger affinity of kappa than lambda. To modify the disease process. Course of the AL amyloid facilitating the removal of amyloid fibers deposit in the tissue. It's going to be a multi center, multi center open label cohort with design selection in patients with mayo stage 12 and three A. L. And it's going to be administered in combination with standard of care which is cyborg D. And D. Aracatuba mom. Just because there is an overlap. One of the things that we've talked about for the past couple of years, there's always doxycycline. So doxycycline has been shown to be beneficial properties in amyloid over the years. In vitro studies in the beta amyloid and in vivo and mouse models and T. T. R. And L. The thought is that it inhibits the matric the mm mp by um the fiber all directed properties. There has been retrospective survival benefits and ailes patients who underwent stem cell transplant and received doxy compared to penicillin. And then also in patients with advanced ale getting treated with concomitant chemotherapy has lowered early mortality when compared to historical controls. And this is a mainstay still in um in our practice. And one of the things that we caution our patients it's very well tolerated. But during the summer we always caution in terms of sunscreen. Um And then also some gi upset and in terms of the other perspectives of this disease um I wanted to also focus because there's a lot of overlap in terms of just the diagnosis and the treatment team. Um Looking at T. T. R. T. T. Are targets of therapy is looking at different processes along it's completely different disease process but in terms of a lot of overlap in terms of misdiagnosis. So when we look at treatments in terms of TT are we're looking at different levels. Are we blocking tt our production at the the MRNA standpoint in terms of blocking protein synthesis. Are we stabilizing the tetra mur? Or are we talking about removal of fiber roles which docks into Duca and another anti monoclonal antibody which is currently now off the market. So in terms of the what brought a lot of um I guess change in this also disease process was the attract trial that looked at to feminist and so to famine is is actually a small molecule and it's in the stabilizer category. Um And it's kind of represented in these little blue dots where it's stabilizing the tetra mur so it does not have the ability to break down two monomers. It was a small trial in terms of but still big in terms of in this population of 441 patients, they looked at wild type and hereditary tT our patients, patients with new york heart one and three they were given placebo 20 and 80 mg and the primary endpoint was death in cardiovascular hospitalization. The key points from this study was survival curve was noted at 18 months. There was a difference noted that six months There's a 33 reduction in the overall mortality And the number needed to treat with 7-8 patients to prevent one death over 2.5 years. And then there was a 32 reduction in rate of hospitalization needed to treat four patients to prevent one hospitalization per year. However, for one thing to note is that patients with New York heart last three did not see the same benefit and there was a noted increase in heart failure hospitalization. Um In terms of the silencers, the other classes, the purpose of their um their mechanism of action is to decrease to decrease if we have the production of mutant and wild type TT R. The goal is to reduce the reduction of unstable monomers or to tremors, the prevention of organ deposition and potential clearance and then stabilization of cardiomyopathy and neuropathy and potential recovery. The two that are FADA approved in this category as participant and Pettersson. Um they both were published in New England Journal 2018 and the same journal which were the results of their trial which was a randomized controlled trial. Very small studies that looked at familiar 80 tr poly neuropathy patients with new york heart. The class greater than two were excluded. Um The patisserie and was I. V. Q. Every three weeks and itis Iran was sub Q. Weekly and their primary endpoint was changed in the N. I. S. Score. So in terms of the landscape of what's currently approved an FDA. Um It's too feminist for wild type cardiomyopathy um And also for hereditary and the participation participant. And and to feminist is for the mixed cardiomyopathy and neuropathy. In terms of other recent trials, there was a G 10 ito's which is the attribute cardiomyopathy. It's also a stabilizer. Um The mechanism was phase three. It's still active but not enrolling. Um not recruiting as an oral. They're looking at wild type and hereditary cardiomyopathy and then a subset of helios a which is vaulted sarin which is a small interfering RNA silencer um which is active but not recruiting any more. That was looking at hereditary PN. Um There was also a small study which was monoclonal antibodies against the misfolded T. T. Are looking at the amyloid fiber. Als unfortunately this trial was stopped from phase one. Um the company decided not to go down this market and this was looking at hereditary cardiomyopathy and peripheral neuropathy. The ongoing trials in this field is Patisserie in Apollo B, which is a silencer. It's currently actively recruiting um and this is looking at wild type and hereditary cardiomyopathy helios be um which is the small interfering RNA. Um and then it's sub Q. Phase three and then there's cardio transform and Euro transform, which is an anti sense aaliyah nucleotide sub Q. And this is also phase three. Just in terms of the landscape of our TT our patients we want to look at and the reason why diagnosis is key. We have different patients in terms of if they can be subclinical new york heart class one versus the symptomatic is 23 and four for those patients. I kind of think of them in three different buckets, are they too early if they're asymptomatic illegal carriers, a mutation without evidence of a cardio genotype? The question is, what do we do with this population in terms of now, as the diagnosis and treatment options do we start up front? What is the serial monitoring for the patients that are just right in terms of the ones who benefit from this disease? New york heart class to genotype positive, imaging and biopsy positive with the preserved F. And then the patients that are too late are the new york heart class four G. F. Are less than 25 unable to emulate. And a modified Bmi less than 600 And one of the key is about, as you guys are all aware and I didn't talk about is the cost of these medications. Um so all of these medications, um which a lot of the clinical trial have been very vocal about is that it's about $225,000 per year. Our patients aren't paying that, but in terms of just the cost of those medications and what is the tax burden in terms of our health care system. And then just to kind of this is a summary slide of looking at what are we looking at for in terms of light chain amyloidosis is and also transfer I written. It's a nice slide in terms of summering everything. If you just wanted one screenshot of everything that's going on regarding the amyloid space. In terms of what we're looking at the reduction of light chain production. Looking at in terms of the inhibition of the amyloid profiles with doxycycline are stabilization with a G 10 def losing all into feminists. Um and then in terms of our inhibition with Itis Iran and Patisserie in um currently P. R. X. Is not on the market. And then in terms of the doxycycline into Duca, Which was our mainstay prior to FADA approval of two feminists. And then um just in terms of a shameless plug in terms of whatever clinical trials that we're having still at penn um in the tt our space. So the Meadows trial is no longer um is completed, we're still doing Apollo be um in terms of looking at it's a 1 to 1 randomization versus placebo. Um and patients that the ways that we reproach that our patients that are considering failing treatment in terms of if they've been onto feminists. Also for Du Nouveau. Um This is actually still open and then also helios be um it's still open for patients that are not onto feminists. And then our cardio transforming the neuro transform is still open. Um I just wanted to end and it has been a great opportunity in terms of working in this space. Um We, in terms of multidisciplinary, in terms of amyloid, um We were we meet weekly um in terms of a multidisciplinary team, in terms of neuro renal and cardiology and where we share patients and doing collaboration, which has actually helped in terms of patient management.