Pelacarsen Failed to Meet Its Primary Endpoint, but the Science Keeps Going

Why Knowing Your Lp(a) Matters

Dr. Michael Koren 0:00

Seth, for people that may have questions about their actual Lp(a) level, what advice would you give them?

Dr. Seth Baum 0:06

Well, first of all, our our guidelines, we were late to do this in the United States, but our our guidelines now are consistent with the other world guidelines, which is everybody needs to know his or her Lp(a). So we can do it at uh at clinicians' offices, we could do it at research sites, um, and we could do it at the Family Heart Foundation, where we have a very robust program uh for um Lp(a) testing with uh care navigators who can help guide individuals uh if they do have elevated Lp(a).

Welcome And The Horizon Headline

Announcer 0:43

Welcome to MedEvidence, where we help you navigate the truth behind medical research with unbiased evidence-proven facts, hosted by cardiologist and top medical researcher, Dr. Michael Koren.

Dr. Michael Koren 0:54

Hello, I'm Dr. Michael Koren, the executive editor for MedEvidence, and I have a great pleasure today of interviewing a friend, a kindred spirit, and an incredibly accomplished lipid investigator, Dr. Seth Baum. Seth is the chairman of the board of the Family Heart Foundation. And Seth is also an investigator and a national lead in a very important study called the Horizon Study using a drug called pelacarsen. And he and I are going to have a discussion about some really important information that came out from this trial recently. Seth, welcome to MedEvidence. Or I should say welcome back to MedEvidence!

Dr. Seth Baum 1:33

It's great to be here. Thanks. Thanks for having me on again.

What “Missed The Endpoint” Means

Dr. Michael Koren 1:36

Absolutely. So let's just jump right in. There was a study called the Horizon Study that you are a big part of, and it came out with an important headline. So why don't you let everybody know what that headline was, and then we'll kind of dig into what that means for people.

Dr. Seth Baum 1:49

Yeah, so so the important headline was that horizon fell to meet its primary endpoint, which is reducing the composite, the uh four-point MACE, which is non-fatal MI [myocardial infarction], non-fatal stroke, cardiovascular death, importantly cardiovascular, not coronary heart disease death. So we can talk about that, and urgent revascularization requiring hospitalization.

Dr. Michael Koren 2:16

Right. And for those not used to clinical trial jargon, MACE stands for major adverse cardiac events or coronary events, as the case may be, but these are the major events that we track during clinical trials. So it fell to me the end point. Oh my God, does this mean that this is a dangerous drug?

Dr. Seth Baum 2:34

It does not mean that it's a dangerous drug at all. What this means, and the top line results didn't mention anything about a safety signal, so I think we should feel comfortable about that. What this means that in this particular setting, this particular study design, this population, this particular drug during this particular time period, and these are all important variables, the drug did not do what we hoped it would do, which is lead to a 20% relative risk reduction in those four elements that I just just mentioned.

Dr. Michael Koren 3:09

Yeah. And so tell just tell us a little bit about your involvement in the background. So this is a study that's been going on for a number of years.

Dr. Seth Baum 3:17

Okay. Yeah. So so I was very involved in the phase two program. I had the good fortune of being on that New England Journal paper, so I was very, very happy with that. Um and the drug uh showed, you know, an 80% reduction in Lp(a) at the highest dose in that study. And then this phase three study, I was very fortunate to be deeply involved as a national leader. I we enrolled the first patient in the world at the Boca [Raton] site for flourish research and very proud of that as well. It's also a very, very important study because Lp(a) is an established causal cardiovascular risk factor. And I and I I want to emphasize that point because there are people wondering now, you know, after these top-line results have been released, is Lp(a) still something they should test for? Is it something that still remains a causal risk factor? And the answer is very, very important. Yes. The, you know, we have in our guidelines test everybody in the country should have LP(a) tested. Fewer than 5% currently have that. And we also have the establishment of a cardiac cardiovascular risk factor based on Hill criteria. And it meets the Hill criteria. The one element of the nine different parts of Hill criteria, the experimentation part, at this point, we don't have that evidence. That does not negate in any way the fact that all these other lines of evidence, including very strong and consistent Mendelian randomization studies, show that Lp(a) does cause vascular disease and cardiovascular events.

Dr. Michael Koren 4:52

So even though this particular product didn't get the results, only on the top line, that's all we know so far, we still, as cardiologists and as people interested in preventing complications of heart disease, we are here to tell you that you should still be focused on this issue and that a lot more information will come out.

Lp(a) Basics And The Triple Threat

Dr. Michael Koren 5:12

So let's jump in a little bit into what pelacarsen is in terms of the class of drug. And so people understand that this is just one type of approach for lowering Lp(a) and that there are a lot of other approaches out there that we're looking at.

Dr. Seth Baum 5:27

Yeah. So so pelacarsen is an antisense oligonucleotide. It's delivered on a monthly basis. It impacts the basically the the creation, translation, creation of the protein Apolipoprotein A. Apo A is a tail on Lp(a), and and by doing this, it decreases Lp(a) levels. I should mention, I think, what Lp(a) is. So Lp(a) is an atherogenic lipoprotein particle. We have various lipoprotein particles. Those that contain a protein called Apo B are all atherogenic and they contain one Apo B per particle. Lp(a) has one Apo B per particle. It's like a very small LDL particle, but it has the addition of a tail. The tail is called Apo A, and Apo A's tail oftentimes will determine the concentration of... Lp(a) particles in the bloodstream. The more Lp(a) particles, the higher the risk. It turns out the shorter tails typically produce more Lp(a) particles than those with longer tails. And that pretty much is just on the basis of production. It's easier for the liver to produce the smaller tails than the longer tails. So, but the bottom line really is what how many Lp(a) particles do we have in the blood? Lp(a) is what we call a triple threat because it's atherogenic, it causes vascular disease, it increases inflammation, and it also increases thrombosis through its homology to plasminogen. So it it has all three of these effects. And there are some studies that indicate that Lp(a) on a particle-to-particle basis, if you were to compare Lp(a) to LDL, Lp(a) is five to six times as atherogenic. So it is a bad player.

Dr. Michael Koren 7:31

Right. Absolutely. And one of the the theories is that the body has a more difficult time getting rid of Lp(a) because it doesn't get picked up by the LDL receptor that is available to get rid of LDL particles. So that's one of the theories. I think you would agree with that theory, although let's jump in a little bit more in terms of the different classes of drugs that we're looking at. So this is called an ASO, an antisense oligonucleotide, as you mentioned. And we're doing work in many research centers around the world on small interfering RNA [siRNA] molecules. Do you think that this result has any implications for what we would expect for these other products that are being tested?

ASO Vs siRNA And The COVID Problem

Dr. Seth Baum 8:15

It's a great question. First of all, everything we're doing today is speculative. We do not have the data to even understand what happened in the trial. So it's hard to know what caused this. There are things outside of the drug that could have caused this null result. So I just want to emphasize it's speculative. And then if you look at the antisense oligonucleotide pelacarsen, and you compare it to the small interfering RNAs, first of all, small interfering RNAs are delivered every three months or every six months. So they have a much longer effect, making them, in a sense, less prone to problems if people don't take doses. And and let's let's remember that this study started. We enrolled the first patient in December of 2019, started right when we were entering COVID. And it went through a really rough time early on in COVID. And so a lot of things happened there that we can expound on that could have influenced the results here. So the drugs, although they, you know, the small interfering RNAs and the antisense oligo nucleotide do the same thing by decreasing the production of ApoA and therefore Lp(a). They have different half-lives and also they have different efficacy. The small interfering RNA drugs will reduce Lp(a) 95 to 99%, whereas pelacarsen reduces it 80%. And it's the absolute reduction in Lp(a) that really is going to end up delivering the result, we think. So there are potential significant differences there.

Dr. Michael Koren 9:54

Sure. And you brought up some really important points. So just to sort of emphasize, the Horizon study had the disadvantage of starting right before COVID, and that created some sloppiness in the study. A lot of sites were actually closed during a period of time when we were doing the study, and then there were some uh disruptions during the course of the study that may have an impact on the results, and we don't have any of that information as of yet.

Dr. Seth Baum 10:20

We Dont! So yeah, and I could really expound on that. I mean, what else happened in COVID? Well, people didn't show up for MIs [heart attacks], we know that, right? So that would be a problem here from an event standpoint. They showed up for heart failure, and this was a cardiovascular disease death endpoint. So they showed up for heart, there were more heart failure deaths actually in COVID. That could have diluted the events, right? So, and COVID was a pro-thrombotic event. So people had PE's [pulmonary embolisms], people had more infarct[tion]s, and that that was not dependent on Lp(a). So all these things could have diluted the events and diminished the ability to have a positive trial.

Dr. Michael Koren 11:02

Right. So a lot to unpack there. So we'll be very anxious to see the details, I'm sure, that we'll get a nice presentation at the American Heart Association meeting and perhaps a full manuscript to really dig into the details. And the details matter for the simple reason is we may find a subgroup within the horizon study that did benefit. And that would be super important and would certainly guide how we approach the next series of clinical trials. Let me just ask you one other question. ASOs [antisense oligonucleotides] work more in the nucleus of the cell versus the siRNAs [small interfering RNAs] that work in the cytoplasm. Do you think that matters at all?

Dr. Seth Baum 11:39

Aaron Powell It's a it's a great point. I I don't know. I don't know the answer to that, but it's a it's a very good observation and question.

Stay In Trials And Keep Enrolling

Dr. Michael Koren 11:48

So let's talk about this from a from a patient experience. So there are two groups of patients I want to focus on because they're looking for advice. So the first group of patients are people who are in clinical trials as we speak that have Lp(a) issues. And what your what would your advice be to those people? Should they reapproach their investigators about maybe getting out of the trials? How would you advise people to deal with this information vis-a-vis their participation in clinical research?

Dr. Seth Baum 12:17

Yeah, absolutely stay in the trial. First of all, being in a cardiovascular outcomes trial, in independent of what's being studied, being in one of these trials, we understand from multiple prior trials actually decreases the rate of events in the placebo arm. Right, right.

Dr. Michael Koren 12:37

So so the protective arm of a clinical trial.

Dr. Seth Baum 12:41

Correct. So we know that being in one of these trials is good for people who have cardiovascular disease. That's number one. Number two, specific to the Lp(a) issue, these drugs really may end up being highly effective. We we cannot infer from the null result for this one trial that the others will be null. The trials are very different. They're very the drugs are different. The trials have different structure. So 100% stay in these trials. In fact, they're still openly enrolling studies. People with high Lp(a) should get into those trials. They should engage. This is the time that we need to double down and increase our efforts to understand how to beat this very, very bad cardiovascular risk factor.

Dr. Michael Koren 13:30

Right. So just to be clear, your advice is if you're in a trial, stay in the trial, including a pelacarsen trial, by the way, the people still getting pelacarsen. And because we don't know if there's a subgroup that may benefit. So your advice is very clear. Whatever trial you're in, stay in it. And then there was a good segue to people who have Lp(a) issues that don't know what to do. And you insinuated they should be searching trials to get the answer. So maybe expound on that a little bit more.

Dr. Seth Baum 13:56

Yeah, I think I I I think they should. So again, we have to go back to what we do know. We know that Lp(a) is a dangerous player. It is an it is a cardiovascular risk factor. And and there is significant evidence that, as I said before, on a per particle basis, it's a much more dangerous thing than LDL. Now, LDL still is bad, and we're not doing as great a job as we should with reducing LDL. We have the tools to do it. So we should all double down on that, too, by the way. That's another thing that came out of this trial. You know, pay attention, get your LDL down. But but but back to the L p(a), yes, the patients should seek out trials. You know, one of the things we understand is that through Mendelian randomization studies, that, you know, the the risk inherent with Lp(a). Well, there are certain studies that that are going to approach even better than these drugs the Mendelian randomization knowledge. And what are they? They're the genetics studies, the gene editing studies that we can look to. Well, think about it. If we can get to people really early on and eliminate the Lp(a) problem, then we're going to really be able to approach what we find in Mendelian randomization. Whereas when we give a person a drug for four, five, six years, it's a small segment of their life and approaching it much later. And it's harder, not, you know, we we hopefully will have great success with these other drugs, but it's harder even to get the effect that's consistent with Mendelian randomization. So stay in and seek out these other trials, these drug trials, and also pay attention and stay tuned for gene editing studies as well.

Gene Editing And Apheresis Options

Dr. Michael Koren 15:42

Yeah, so let's talk about that. We we think gene editing studies are on the horizon for Lp(a). We're already involved in these studies for LDL and for triglycerides, and starting studies with gene editing for hypertension and a bunch of other things. So it sounds like your advice is to move forward with full force in these gene editing studies for Lp(a). And in fact, it's really intriguing for patients that don't have an easy answer right now to get involved in these programs. Don't want to put words in your mouth, but that's what I'm hearing.

Dr. Seth Baum 16:10

No, and I agree with that. I I also want to mention apheresis, by the way, for people who have markedly elevated Lp(a)'s who've had cardiovascular events. I know there are only 70 programs or so in the country right now, but we have a ton of observational evidence in Lp(a) that reducing Lp(a) through apheresis reduces events. Now, the the patients in those studies served as their own controls. You compare it to event rates before and after being on apheresis, but they're very, very consistent that there's somewhere in the 60 to 90 percent reduction of events uh that have been seen throughout these studies. So if you if you do have elevated Lp(a) and you're looking for something, you know, speak to your physician and and seek out perhaps a lipoprotein apheresis program.

Dr. Michael Koren 16:59

Yeah. And again, that's sort of a dialysis-like technique where your blood is cleaned of the particle. So let's talk about one other little thing, which is not so little, but it may be really important.

Why Risk Varies And What You Control

Dr. Michael Koren 17:10

And I'll be super interested in looking at the horizon results to see if we can tease this out. When I first learned about Lp(a) decades ago, it seemed like a type of risk factor that almost predetermined that you're going to have a bad outcome from cardiovascular disease. But now, as we enroll in these clinical trials, we find that there is diversity in patients even with high Lp(a), and we're finding people that, for whatever reason, seem to not get atherosclerosis. Any insights for people listening to us about that? What category do you fall in? And any insights for designing clinical trials in the future that will hopefully concentrate the risk in these studies so that we can show hopefully a benefit?

Dr. Seth Baum 17:52

I love that. That's interesting. Another good point, a good question. You know, we've seen this with LDL too. I've seen it even, uh believe it or not, an FH [familial high cholesterol]. I once had a, I think she was 35 or 40-year-old woman with an LDL uh 400 referred for apheresis. She had not a she had not a fleck, not a speck of of atherosclerosis, right? So we we do see we see this happen. We don't completely understand it. We see with Lp(a) as well. What I would say to people with elevated Lp(a) is we do not know why some people have events and others do not. But what we do know is the more other issues, the more other comorbidities you have. For example, in FH, if you have familial hypercholesterolemia, there's a greater likelihood your Lp(a) will be elevated. And there is independent risk that comes from that. So your risk is that it's like a double whammy, basically. You know, you really need to pay attention. And now what can you do? Well, you know, to your point, you can enter a trial, you can do that, but you can also drop your LDL as low as you can get it to and and decrease all other cardiovascular risk factors to help mitigate the risk associated with Lp(a).

Testing Access And Threshold Questions

Dr. Michael Koren 19:07

Seth, for people that may have questions about their actual Lp(a) level, what advice would you give them?

Dr. Seth Baum 19:14

Okay, well, first of all, our our our guidelines, we were late to do this in the United States, but our our guidelines now are consistent with the other world guidelines, which is everybody needs to know his or her Lp(a). So we can do it at clinicians' offices, we could do it at research sites, and we could do it at the Family Heart Foundation, where we have a very robust program for Lp(a) testing with care navigators who can help guide individuals if they do have elevated Lp(a).

Dr. Michael Koren 19:49

Seth, one of the questions that have come up in my discussions with other lipid experts is whether or not the threshold level for Lp(a) in the horizon study was too low. I don't know if you have any comments about that vis-a-vis some of the other studies that are being done that are using higher thresholds.

Dr. Seth Baum 20:07

Yeah. ... Yes, since we're looking for an absolute reduction in Lp(a) levels, right, as as as the driver of success here in reduction of events, starting at a lower level with a less potent drug gives you less opportunity to achieve those large absolute reductions in Lp(a). So it certainly could be an issue here.

Don’t Despair And Next Steps

Dr. Michael Koren 20:47

Seth, those are incredible insights. Uh, thank you so much. Any final parting words on for people, mostly patients that are listening to us and still may have some confusion and questions about how to deal with their Lp(a).

Dr. Seth Baum 21:01

Yeah, so I would say, look, you know, these top line results were released on Friday. Lp(a) today is the same as it was on Thursday before the release. We it's it's it's a very bad cardiovascular risk factor. We know that. We what the unfortunate part is we're right now we're left with uh a drug study that failed to meet its primary endpoint. We don't know any more than that. So I would say really do everything the same as you were doing beforehand, with potentially even more. So go you know, speak to your clinician, make sure your other risk factors are are are well controlled, LDL in particular, because that's you know, in the United States very poorly controlled. And then look at look for another trial, stay in a trial if you're in a trial, and and just stay the course, don't despair. This is science, it's iterative. We understand this from prior studies that you know it's it's some sometimes we fail and then we succeed later. So do not despair.

Dr. Michael Koren 22:07

Seth, thank you so much for your insights, and thank you for participating in this really important program from MedEvidence!

Announcer 22:14

Thank you for having me, Mike. Thanks for joining the MedEvidence Podcast. To learn more, head over to Metevidence.com or subscribe to our podcast on your favorite podcast platform.