Continuing with Part 3 of Drs. Michael Koren and Dennis Leahy discussion on MedEvidence exploring Lipoprotein A treatments. Dr. Leahy shares his personal experience with Lp(a), and the duo delve into cutting-edge treatments and research. Tune in to learn more about this lesser known condition and possible treatment options.
Dr. Dennis Leahy is a retired interventional cardiologist living in San Diego. He received his education from Princeton University and Columbia University and his residency at the University of California. In addition to enjoying the opportunity to surf and golf, he has maintained a personal and professional interest in Lipoprotein A research and treatment.
Michael J. Koren, MD, is a practicing cardiologist and Chief Executive Officer at Jacksonville Center for Clinical Research, which conducts clinical trials at 7 locations in Florida. He received his medical degree cum laude at Harvard Medical School and completed his residency in internal medicine and fellowship in cardiology at New York Hospital/Memorial Sloan-Kettering Cancer Center/Cornell Medical Center.
He is a fellow of the American College of Cardiology, fellow and two-time president of the Academy of Physicians in Clinical Research, and the regional chapter of the American Heart Association.
Dr. Koren has served as an Investigator in over 2,000 trials and as the international lead investigator for many multi-centered trials including ALLIANCE, ROLE, TREAT to TARGET, OSLER, and MENDEL studies. He has written and co-authored over 100 peer-reviewed articles and been published in the most prestigious medical journals.
Continuing with Part 3 of Drs. Michael Koren and Dennis Leahy discussion on MedEvidence exploring Lipoprotein A treatments. Dr. Leahy shares his personal experience with Lp(a), and the duo delve into cutting-edge treatments and research. Tune in to learn more about this lesser known condition and possible treatment options.
Dr. Dennis Leahy is a retired interventional cardiologist living in San Diego. He received his education from Princeton University and Columbia University and his residency at the University of California. In addition to enjoying the opportunity to surf and golf, he has maintained a personal and professional interest in Lipoprotein A research and treatment.
Michael J. Koren, MD, is a practicing cardiologist and Chief Executive Officer at Jacksonville Center for Clinical Research, which conducts clinical trials at 7 locations in Florida. He received his medical degree cum laude at Harvard Medical School and completed his residency in internal medicine and fellowship in cardiology at New York Hospital/Memorial Sloan-Kettering Cancer Center/Cornell Medical Center.
He is a fellow of the American College of Cardiology, fellow and two-time president of the Academy of Physicians in Clinical Research, and the regional chapter of the American Heart Association.
Dr. Koren has served as an Investigator in over 2,000 trials and as the international lead investigator for many multi-centered trials including ALLIANCE, ROLE, TREAT to TARGET, OSLER, and MENDEL studies. He has written and co-authored over 100 peer-reviewed articles and been published in the most prestigious medical journals.
Welcome to MedEvidence, where we help you navigate the truth behind medical research with unbiased, evidence-proven facts, powered by Encore Research Group and hosted by cardiologist and top medical researcher, Dr Michael Koren.
Speaker 2:
Hi, I'm Dr Michael Koren and I'm delighted to lead another episode of MedEvidence, episode of Mid-Evidence, and today I had the great pleasure of talking to Dr Dennis Leahy, who is a colleague and actually not only an interventional cardiologist, but an interventional cardiologist that has dealt with the problem of lipoprotein little a. In our previous discussions we talked about his history and now we're leading to the part of his history where he had to decide about what treatment modalities to pursue and fortunately, he made contact with Dr Sam Samikis, who's considered an expert in this field and somebody who's been very active in therapies that are targeted against lipoprotein little a. So, dennis, I'll let you pick up the story from there. So I think you said you met Sam in 2017, is that correct?
Speaker 1:
So, yeah, part of the good fortune of my story. I guess the bad fortune is I have this problem, but the good fortune is I've had access to world-class healthcare and it's really gotten me through all this. So I met with Sam and he was starting.
Speaker 2:
I was going to interrupt you for a second just to make sure we update the audience. So Dennis had coronary artery bypass surgery after a number of stents were placed. Dennis had coronary artery bypass surgery after a number of stents were placed and then a few years later he needed a carotid endarterectomy to repair a blockage in his left carotid artery that caused a little mini stroke. So he certainly had many, many complications of lipoprotein delay, despite having no other cardiovascular risk factors, being a very active person and taking statin therapy. So take it from there, dennis.
Speaker 1:
So Sam was working with Ionis Pharmaceuticals where they had developed this ASO or antisense oligonucleotide treatment for LP-LLA, which is a gene-slowing approach to try to suppress LP-LLA production. They'd had one successful phase two trial and they were starting another one. And this is right about the time. I just happened to consult with Sam and he offered the entry to the trial to me and it sounded like a great option because, unlike other trials where it's frequently a 50-50 chance of getting active treatment, this was a dosing trial, so I had a five out of six chance of actually being on an active drug. So I was in that study for one year with, as you know, successful and impressive suppression of LP delay production. I think I was on a once every two-week injection, subcutaneous injection, very simple procedure which has been shown to be quite safe with minimal side effects.
Speaker 2:
And this is the molecule that we call pelicarsin. Now is that correct, right? And you know, antisense oligonucleotide that actually prevents the production of the protein that is essential for the assembly of lipoprotein delay in the nucleus of the hepatocytes. I should mean right outside the nucleus of the hepatocytes. So that's a fascinating technology and really, really exciting and so exciting that, as I understand it, novartis bought the product.
Speaker 1:
Novartis, of course, is in, hopefully towards the end of a trial, a major, major trial that will be a really landmark kind of pivotal trial of whether these things are going to result in lower incidence of the cardiovascular events by suppressing LLP. Delay production.
Speaker 2:
Yeah, and we're participating in that trial as we speak. It's fully enrolled as I understand it. But here in Florida we're very excited about the possibilities and it looks like that product could be the first in class to actually treat the real underlying issue of lipoprotein Lele. But keep on going with your story. So you did well in the trial. Do you remember how it?
Speaker 1:
actually affected your numbers, yeah, my numbers. You know I had a 70, 80% suppression of LP to lay levels. You know my baseline levels are usually 120 to 130. And they came down to, you know, 50, 40, very close to the upper limits of normal. And it was, you know, just nothing for me to do. It was really simple. And it was, you know, just nothing for me to do. It was really simple.
Speaker 2:
Again, I bring that up because, in contrast, to apheresis, which is what I've been doing for the past few years. It's quite a different approach so it went well Interesting. So you didn't have any injection reaction things or any concerns of using these type of technologies. No, no problems at all. Okay, so then you went to apheresis. So for everybody out there, that's kind of like a dialysis type therapy where you have to have your blood filtered, basically. So why don't you tell us how you ended up doing apheresis?
Speaker 1:
Yeah, so just to get back to the timeline, so I was in the trial for most of 2017, part of 2018, and then stopped it and just was on statins and aspirin. On statins and aspirin, and then in 2020, surfing had an episode of chest pain. My graphs now are, you know, 12 years old, which is you know you might expect I mean, you're just waiting for that moment and I had a stress test which was pretty unremarkable. There's a very, very minor area of hypoperfusion in the right corary distribution. So I had an angiogram and again, credit to my friend, my former climbing partner and surfing partner, who is my cardiac surgeon the grafts looked fantastic and there was a focal lesion in my right coronary artery that would lend itself to stenting. You know, 100% of the time Now.
Speaker 1:
You know my history with stents was miserable. I was very, very concerned about, you know, going down that pathway again, and so Sam and I met and talked and thought well, at least around the time I'm going to have the stent placed, I want to be on apheresis. I want my LP little a level as low as possible, because I'm virtually certain that was what was the cause of my restenosis problem. I'd never seen anybody restenose stents like I had, and I think it was all LP, little a mediated. So that's when I went on apheresis, which I've been doing now for three years.
Speaker 2:
Nice and tell us a little bit more about that. How often do you get it? Is it a hassle? What are your numbers?
Speaker 1:
Well, to answer the second question first, it is a hassle, it's a pretty big undertaking. As you mentioned earlier, it's a way of filtering the lipoproteins out of your blood, the low-density ones particularly. But because this problem is genetically mediated, your body knows how much Lp-Lil-A it wants to produce and it keeps producing it. So when you go to your Lp-Lil-A treatment, your Lp-Lil-A level at 9 in the morning is 130. Treatment, your LP-Lil-A level at nine in the morning is 130. And when you finish, somewhere between three or four hours after the treatment that's how long the treatment lasts then your LP-Lil-A level's down to 30. Two weeks later it's back to 120. So it's a process that's been, as you know, it's been around for a long time, particularly in Germany. Processes have been, as you know, it's been around for a long time, particularly in Germany, where most of the research was done. And the thing about apheresis it is very, very good data.
Speaker 2:
It's observational because there's no way to double blind an apheresis study. At least, if you have any ethics, it could be a little squirrely for an IRB on that one.
Speaker 1:
It would be a rare institution that would go for that, but it did. You know? Observational studies show that repeated cardiac events were lowered substantially, actually in the range of 70%, in people who are getting apheresis regularly. I think in Germany they did it every week, which would dominate your life. So I did it every two weeks for about a year and a half, and even that was getting kind of to me a bit. It was basically a lost day and it was a lot. So I've done it every third week more recently.
Speaker 2:
And so you're doing that.
Speaker 1:
Any further complications help wise? No, I had no issues. Everything's been fine. You're doing that. Any further complications, health?
Speaker 2:
wise. Everything's been fine. Um. Are you tracking anything else other than just the lpa levels? Uh any inflammatory markers or other assessment of your coronary anatomy?
Speaker 1:
I think you know, I think the whole discussion inflammatory markers and lp delay is a is a big issue, I think. Uh, that will probably enter into how and who should be treated for LP the lay. How about your carotids?
Speaker 2:
Have you had those looked at?
Speaker 1:
Yeah, my carotids get checked every six months. So I've got about a 60% to 70% right carotid lesion. It's been completely stable since 2017. My current regimen I'm actually changing it sam and I talked to a couple weeks ago and I've decided to. I've started rapatha uh, the bcsk9 inhibitor, and I'm kind of thinking, if that achieves what it has in the first two um numbers that I've checked since I've been on it, I may opt out of apheresis because it's actually lowered my. I've been lucky. I'm kind of one of the people. It suppressed my Lp-Lol-A by about 35% and which I think on average, is probably what I'm getting out of apheresis. So it's a thought.
Speaker 2:
Yeah, the PCSK9 inhibitors are really the first class that have some consistent efficacy against LPA and to the point you're making, the studies are showing somewhere between a 20% and 35% reduction in LPA in folks in your situation and, of course, really, really nice reductions of LDL up to 60%. So that is truly a breakthrough in terms of treating this dyslipidemia. But 30% is not nearly what we're seeing with some of the newer drugs that we'll talk about momentarily. But I had just a couple other quick questions to the point. On apheresis, yes, was there any concern about this fluctuation of the LPA level? Some people have talked about that? Is it more important to be consistently low or just preventing your body from being exposed to high question.
Speaker 1:
It's a good question, but I think the general idea is the lower the better, and you'd like to see it continuously low and not have to be reintervening every couple of weeks to get it down. A linear increase between visits or not. But as I said, I think probably in my case I'd usually start at 120, 130 and finish at 30. And so you know probably the mean. Just if I was thinking of it linear, the mean LP delay level would be about 70. I think the average around 80.
Speaker 2:
And what was your LDL? Ldl has always been, because I've been pretty high dose statins.
Speaker 1:
My LDL baseline is about 55, and then it would go down to about 11 at the end of an apheresis treatment.
Speaker 2:
Yeah, and apheresis can be used for familial hypercholesterolemia also. So that's just LDL problems without the LPA problem. But a lot of people actually have both LDL and LPA problems and apheresis may be an attractive option for those folks. So I'm going to I'm just going to throw one thing out there and then we'll take a quick break. But when we talk about these different therapies they have different mechanisms. So we just talked about apheresis, which is basically a filtering mechanism that's been around for a while. That. I was first exposed to that actually as a cardiology fellow. During my cardiology fellowship in the late 80s, early 90s we had a program where apheresis was done for severe lipid problems and, as I mentioned, there wasn't great buy-in amongst the cardiologists at that time and it was actually done at the Rogeson Institute of Cornell by the nephrologists. So literally we had cardiologists having to refer to nephrologists to get treatment of this problem back in that time period. But probably that was the only thing that was effective.
Speaker 2:
Other modalities have not panned out particularly well. We thought that niacin may have some nice effects on LPA, but unfortunately all the clinical trials with niacin really just didn't pan out particularly well for patients in terms of reducing adverse outcomes, so that kind of fell out of favor. But then the PCSK9 drugs and the two antibodies that are on the market are Proliuent and Repath, as you mentioned, and what they do is they lower LDL tremendously by up-regulating the effects of the LDL receptor so that the LDL receptor can remove these bad lipoproteins from the circulation. The thought prior to the Repatha data, quite frankly, was that the LDL receptor did not work at all to remove lipoprotein little a. And to sort of remind the audience, lipoprotein littlea is basically an LDL molecule that has some extra protein components that make it a molecule that the LDL receptor cannot remove from the circulation. Therefore it just hangs around and causes havoc and potentially inflammation.
Speaker 2:
But interestingly, with Repatha and Pliwent, the antibodies, we're seeing that when you got the LDL down far enough, then the affinity for the LDL receptor may get to a point where the LDL receptor can actually remove some LPA. So that was interesting and maybe the mechanism that's operating in your case. But again, unfortunately that's still only about a 30% reduction and most people in your situation need way more than that. Just in fairness, inclisrin, which is another drug, small interfering RNA that also uses a PCSK9 mechanism, is also effective against LPA Maybe not quite as much as the antibodies, but again, they haven't really been compared head to head so I won't speculate on that. But bottom line is that we have something out there that does have some effect on LPA, but not nearly as much as what we think the next generation will hold. So with that thought we're going to take a quick break.
Speaker 1:
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