# Marios Georgakis: Why Did Two Major Clinical Trials for Heart Disease Fail?

An episode of [Ground Truths](https://invisiblenetwork.ai/podcast/1728526108), 14 Sep 2026, 1 h 08 min.

Audio: https://api.substack.com/feed/podcast/213058240/482064460b59f4174b050ce05f3dcf6c.mp3

In recent weeks the results (announced by press release) of 2 major placebo-controlled randomized trials—ZEUS, testing an interleukin-6 (IL-6) blocker vs inflammation, and HORIZON, testing a drug to lower Lp(a), indicated failure to achieve their primary endpoint. Are we maxxed out for new treatments vs heart disease, as this article in the WSJ (←gift link) today asserts? “Cardiovascular drug development is starting to look a bit like the modern oil industry. The easy wells have been tapped. What’s left is in deep water: expensive, technically perilous and less likely to strike oil.” Or is it more complicated? Are the trial results and reasons for failure different? I wrote a recent Ground Truths —The Coronary Artery Inflammation Controversy— on the data (what has been released to date) and my take. But I wanted to vet this with another physician-scientist who is studying atherosclerosis and turned to Prof Marios Georgakis, from the University of Munich, who as I mentioned in the previous piece, wrote a brilliant analysis of ZEUS and is also doing writing about HORIZON. Many years ago we went through a “CV winter” when the biopharma companies largely shunned doing clinical trials for heart disease. They thought the field had been maxxed out. After a lapse of several years, there have many trials undertaken with positive results and substantial progress for better treatments vs heart disease. Both Marios and I remain optimistic that we are a long way from maxing out, as you’ll learn from the podcast. Heart disease is the number one global killer, for both men and women. That’s despite all the progress that has been made to date. Thanks for your support of Ground Truths and to Dr. Julie Kellogg, Vau Geha, Ralph Horwitz, Jessica Coffman, Michael G. Levin, MD, and mopre than 400 others for tuning into my live video with Marios Georgakis! ********************************** Ground Truths has 215,000 subscribers from every US state and 214 countries. There are over 310,000 followers of Ground Truths so nearly 100,000 folks who can easily convert to be free subscribers. Please consider doing that…it’s free. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. If you’re not a subscriber, please join! If you found this interesting PLEASE share it! The proceeds from all voluntary paid subscriptions go to support our summer internship program. It enabled us to accept and support a record number of 62 summer interns that joined us in 2026! These are high school, college and medical students selected from thousands of applicants. We couldn’t do this expanded program without the funds coming in through Ground Truths. Thank you! Get full access to Ground Truths at erictopol.substack.com/subscribe

## Transcript

[0:01] SPEAKER_01: Okay, I'm Eric Topol, and this is Ground Truths.
[0:03] SPEAKER_01: I'm thrilled that you're joining us today.
[0:06] SPEAKER_01: I have the real delight to have this discussion with Marius Juridakis at
[0:13] SPEAKER_01: the University of Munich,
[0:15] SPEAKER_01: who is a physician scientist,
[0:17] SPEAKER_01: actually a neurologist who studies atherosclerosis,
[0:21] SPEAKER_01: genomics,
[0:22] SPEAKER_01: particularly the cerebrovascular,
[0:24] SPEAKER_01: but he certainly is tuned into the coronary and atherosclerosis anywhere in
[0:27] SPEAKER_01: the body.
[0:29] SPEAKER_01: And he wrote a book in his own Substack called The Codon about the Zeus trial.
[0:36] SPEAKER_01: And we're going to discuss these two trials, big trials, pivotal trials that failed.
[0:42] SPEAKER_01: So welcome, Marius.
[0:44] SPEAKER_02: Thank you, Eric.
[0:45] SPEAKER_02: Nice to be here.
[0:46] SPEAKER_02: Thank you again for the invite.
[0:48] SPEAKER_01: Yeah, no, it's going to be great.
[0:50] SPEAKER_01: So...
[0:53] SPEAKER_01: This is kind of unprecedented in my many decades as a cardiologist
[0:58] SPEAKER_01: to see two pivotal trials,
[1:00] SPEAKER_01: one with over 6,000 patients, one with over 8,000 patients, and they both failed.
[1:09] SPEAKER_01: And maybe there's common threads here, maybe not.
[1:13] SPEAKER_01: But let's first,
[1:14] SPEAKER_01: before we get into that,
[1:16] SPEAKER_01: talk about atherosclerosis and inflammation and What's your sense about,
[1:22] SPEAKER_01: you know,
[1:22] SPEAKER_01: people are talking, oh, well, this proves the inflammation hypothesis is wrong.
[1:28] SPEAKER_01: What's your sense about the process of atherosclerosis?
[1:34] SPEAKER_02: Yes.
[1:35] SPEAKER_02: Thank you, Eric.
[1:36] SPEAKER_02: So, I think...
[1:41] SPEAKER_02: The history of inflammation and atherosclerosis actually goes a little bit, right?
[1:46] SPEAKER_02: So over 100 years in principle.
[1:48] SPEAKER_02: It was the beginning of the 20th century when Nikolai Anitschkev,
[1:53] SPEAKER_02: a pathologist who fed rabbits with high levels of cholesterol,
[1:59] SPEAKER_02: and he observed under his microscope atherosclerotic lesions in their aortas at
[2:05] SPEAKER_02: the time.
[2:06] SPEAKER_02: He was able to see this, what we call today, foam cells, right?
[2:09] SPEAKER_02: So macrophages filled with cholesterol and lipids.
[2:14] SPEAKER_02: And he already assumed at the time that these are in principle phagocytes, macrophages.
[2:20] SPEAKER_02: So this was the first connection to an immune response, if you wish.
[2:26] SPEAKER_02: And that's already early 20th century, so over 100 years ago.
[2:31] SPEAKER_02: And of course, since then, we've done massive progress, right?
[2:35] SPEAKER_02: After that,
[2:37] SPEAKER_02: for decades,
[2:38] SPEAKER_02: immunohydemical studies confirmed in principle that those are immune cells,
[2:41] SPEAKER_02: macrophages, T-cells.
[2:44] SPEAKER_02: Through quantification of cytokines within human plaques,
[2:49] SPEAKER_02: we were able to see that there are high levels of inflammatory mediators.
[2:54] SPEAKER_02: And then even more recently,
[2:56] SPEAKER_02: with high-throughput technologies like single-cell RNA sequencing,
[3:00] SPEAKER_02: special transcriptomics,
[3:02] SPEAKER_02: we just came close to Recognize the very complex immune microenvironment.
[3:09] SPEAKER_02: I mean, we're talking about multiple different types of macrophages,
[3:12] SPEAKER_02: T-cells, neutrophils, mast cells, dendritic cells.
[3:18] SPEAKER_02: And so it's a really complex and mature immune microenvironment.
[3:22] SPEAKER_02: And so I don't believe that anybody doubts that inflammation
[3:26] SPEAKER_02: and inflammatory response is actually taking place within the vessels,
[3:31] SPEAKER_02: within the cells.
[3:34] SPEAKER_00: Atherosclerotic plaques.
[3:35] SPEAKER_02: But I think the big question was always
[3:38] SPEAKER_02: whether targeting these processes would actually lead to any kind
[3:44] SPEAKER_02: of therapeutic benefit.
[3:47] SPEAKER_02: Yeah.
[3:48] SPEAKER_01: That's good.
[3:49] SPEAKER_01: I think no one will question, although some did.
[3:53] SPEAKER_01: And like,
[3:54] SPEAKER_01: for example,
[3:54] SPEAKER_01: in the New York Times coverage of this Zeus trial,
[3:57] SPEAKER_01: he said, oh, well, the inflammation hypothesis is wrong.
[4:00] SPEAKER_01: It's not that there's lacking inflammation in arteries with atherosclerosis.
[4:05] SPEAKER_01: It's just that we haven't found,
[4:07] SPEAKER_01: at least so far,
[4:09] SPEAKER_01: A target of inflammation that is going to be safe and highly effective.
[4:13] SPEAKER_01: So also, I want to mention all those that are joined.
[4:17] SPEAKER_01: If you have any questions for Marios, don't hesitate to put them in the message.
[4:21] SPEAKER_01: I'll try to get to them as we move along.
[4:24] SPEAKER_01: All right.
[4:25] SPEAKER_01: So we established that inflammation is a big part of atherosclerosis.
[4:29] SPEAKER_01: And in fact,
[4:30] SPEAKER_01: even a paper this week was about the autoimmune aspects of this whole condition,
[4:36] SPEAKER_01: which is interesting and But let's get into the idea that we have these markers,
[4:44] SPEAKER_01: okay?
[4:46] SPEAKER_01: High sensitivity CRP has been out there for a couple of decades.
[4:51] SPEAKER_01: We got Paul Richter.
[4:52] SPEAKER_01: That's all he talks about is high sensitivity CRP.
[4:55] SPEAKER_01: We have interleukin-6 that can be measured but isn't usually measured clinically
[5:00] SPEAKER_01: so much as HSR-CRP.
[5:03] SPEAKER_00: And, of course, we have the lipids.
[5:05] SPEAKER_00: We have LDL.
[5:08] SPEAKER_01: HDL, triglyceride, ApoB, and LP little A.
[5:14] SPEAKER_01: This is what we have from blood tests.
[5:17] SPEAKER_01: What do these blood tests tell us?
[5:20] SPEAKER_02: Yes, so it's been,
[5:23] SPEAKER_02: as you said,
[5:25] SPEAKER_02: it's been now,
[5:26] SPEAKER_02: I think,
[5:26] SPEAKER_02: over two decades that
[5:29] SPEAKER_02: the first large-scale epidemiological studies actually assessed The relationship
[5:36] SPEAKER_02: of high sensitivity seriactic protein levels in the blood with risk
[5:40] SPEAKER_02: of cardiovascular disease and actually so the pretty robust associations, right?
[5:47] SPEAKER_02: So both case control studies later on,
[5:50] SPEAKER_02: also prospective cohort studies suggesting that people who have high levels
[5:56] SPEAKER_02: of seriactic protein,
[5:58] SPEAKER_02: if you follow the map for And in principle,
[6:01] SPEAKER_02: later on, more or less, we came to similar conclusions for interleukin-6 levels.
[6:05] SPEAKER_02: So also interleukin-6 measuring in blood.
[6:19] SPEAKER_02: Both in primary prevention,
[6:20] SPEAKER_02: so people who don't have cardiovascular disease,
[6:22] SPEAKER_02: but also in secondary prevention settings,
[6:24] SPEAKER_02: people who do have cardiovascular disease,
[6:26] SPEAKER_02: they seem to be predictive of future cardiovascular events.
[6:30] SPEAKER_02: And this seems to hold true even
[6:33] SPEAKER_02: after we statistically adjust other cardiovascular risk factors,
[6:40] SPEAKER_02: including the markers you mentioned,
[6:43] SPEAKER_02: LDL cholesterol,
[6:44] SPEAKER_02: HDL cholesterol,
[6:45] SPEAKER_02: triglyceride levels,
[6:46] SPEAKER_02: but also Other comorbidities that we know,
[6:50] SPEAKER_02: cardiovascular risk, like type 2 diabetes, blood pressure, BMI.
[6:56] SPEAKER_02: So these associations have been out there for several decades.
[7:03] SPEAKER_02: And of course, it's the question, what do they tell us, I think, in two different dimensions?
[7:08] SPEAKER_02: One,
[7:10] SPEAKER_02: can we interpret them in a way that they represent markers of vascular inflammation,
[7:16] SPEAKER_02: if you wish?
[7:17] SPEAKER_02: And on the one hand and on the other hand,
[7:19] SPEAKER_02: can it mean that these very same markers,
[7:22] SPEAKER_02: these molecules could be potentially with causal mediators of atherosclerosis and
[7:27] SPEAKER_02: so potentially promising therapeutic targets?
[7:33] SPEAKER_01: You just said the magic word, causal, right?
[7:36] SPEAKER_01: That's the big deal.
[7:37] SPEAKER_01: So LDL, cholesterol,
[7:40] SPEAKER_01: has panned out to be an extraordinary surrogate,
[7:43] SPEAKER_01: perhaps one of the best surrogates that we know in all of medicines.
[7:46] SPEAKER_01: Because everything that has lowered LDL,
[7:48] SPEAKER_01: whether it's statins, PCSK9,
[7:51] SPEAKER_01: ezetimibe,
[7:52] SPEAKER_01: I mean, you know, all these different things have correlated with improved outcomes.
[7:58] SPEAKER_01: But we saw HDL, which has also been associated with low HDL, with atherosclerosis.
[8:07] SPEAKER_01: And trials were done, like niacin and others, to raise HDL.
[8:12] SPEAKER_01: They failed.
[8:13] SPEAKER_01: Similarly with triglycerides, high triglycerides.
[8:16] SPEAKER_01: So what is causal here?
[8:19] SPEAKER_01: Now, you use a technique, as other genomicists do and researchers, Mendelian randomization.
[8:28] SPEAKER_01: With Mendelian randomization,
[8:29] SPEAKER_01: could you explain for the uninitiated what that is and whether
[8:34] SPEAKER_01: or not things like LP little a, Hscrp, um,
[8:40] SPEAKER_01: And interleukin-6 have ever been demonstrated to be causal
[8:44] SPEAKER_01: through Mendelian civilization.
[8:48] SPEAKER_02: Yeah, so as you mentioned,
[8:51] SPEAKER_02: the question of causality,
[8:53] SPEAKER_02: I think, is an interesting one with regards to therapeutic development, right?
[8:57] SPEAKER_02: So the idea is that if a molecule,
[9:01] SPEAKER_02: if a mechanism is causal for causality,
[9:05] SPEAKER_02: Cardiovascular disease progression, atherosclerosis development.
[9:08] SPEAKER_02: And it means that if we target this mechanism,
[9:13] SPEAKER_02: we should expect benefits in cardiovascular history, the actual clinical benefits.
[9:17] SPEAKER_02: And the problem we have is that with the epidemiological studies I mentioned before,
[9:22] SPEAKER_02: these are classical observational studies.
[9:25] SPEAKER_02: So the problem of these studies is what we call confounding.
[9:31] SPEAKER_02: So if we take,
[9:32] SPEAKER_02: for example,
[9:32] SPEAKER_02: let's say interleukin-6 levels in the blood,
[9:35] SPEAKER_02: We measure it in a big population and then try to associate it with outcomes.
[9:40] SPEAKER_02: We know that the groups of people who have high IL-6 versus low IL-6 differ not only
[9:47] SPEAKER_02: in terms of IL-6 levels,
[9:48] SPEAKER_02: but also in terms of other multiple confounding factors, right?
[9:52] SPEAKER_02: And these confounding factors might also be associated with cardiovascular risk.
[9:57] SPEAKER_02: So it makes it very,
[9:58] SPEAKER_02: very hard to disentangle if the association we see is in principle reflecting
[10:03] SPEAKER_02: a really causal association or not.
[10:05] SPEAKER_02: No matter how much we adjust with statistical methods,
[10:08] SPEAKER_02: because there always will be remaining a so-called unmeasured confounding,
[10:12] SPEAKER_02: like a variation we cannot measure with the methods we have.
[10:16] SPEAKER_02: And the idea of Mendelian randomization is at its core a very, very simple one.
[10:22] SPEAKER_02: And it dictates that if a mechanism is causal for the pathogenesis of a disease,
[10:29] SPEAKER_02: then genetic variation that interferes with this mechanism should also
[10:39] SPEAKER_02: So if we can find a genetic variant or ideally more than one genetic variant
[10:44] SPEAKER_02: that influence the mechanism we are interested in,
[10:46] SPEAKER_02: let's say IL-6 signaling reliably,
[10:50] SPEAKER_02: then we can go take this variant and go and test if it is associated with the risk
[10:54] SPEAKER_02: of cardiovascular disease.
[10:56] SPEAKER_02: And if it does, Then under specific assumptions, we can say that this is probably causal.
[11:03] SPEAKER_02: Why do we say that?
[11:04] SPEAKER_02: Because this approach is less biased as compared to classical epidemiology
[11:11] SPEAKER_02: because people carry their genetic variants from birth.
[11:16] SPEAKER_02: It cannot be that our diet has influenced our genetic variants.
[11:20] SPEAKER_02: It cannot be that our LDL levels have influenced our genetic variants.
[11:24] SPEAKER_02: And so theoretically,
[11:27] SPEAKER_02: the groups of folks that differ in terms
[11:30] SPEAKER_02: of this genetic variant should be otherwise kind of equal.
[11:36] SPEAKER_02: So in other words,
[11:38] SPEAKER_02: in the same way that people in the population might differ because
[11:43] SPEAKER_02: of their genetic architecture in terms of height,
[11:46] SPEAKER_02: some people are shorter, some people are taller, in the same way...
[11:51] SPEAKER_02: Some people have higher or lower activity or file signaling activity as encoded
[11:56] SPEAKER_02: within their genome.
[11:58] SPEAKER_02: And we can then go and leverage that using modern big data sets and go and explore
[12:04] SPEAKER_02: if this is associated with the risk of cardiovascular disease.
[12:09] SPEAKER_02: And the reason why this is interesting in this particular case,
[12:13] SPEAKER_02: particularly in cardiovascular disease,
[12:14] SPEAKER_02: this has served us so far or had served us so far Pretty well in terms of finding,
[12:22] SPEAKER_02: as you said, causal drivers that can be translated into efficacious
[12:29] SPEAKER_02: therapies.
[12:32] SPEAKER_02: So when we do this exercise for LDL cholesterol,
[12:37] SPEAKER_02: no matter what target we select that is,
[12:41] SPEAKER_02: Actually, we use our medications target to lower LDL cholesterol.
[12:45] SPEAKER_02: If we find variation there,
[12:46] SPEAKER_02: any variant that lowers LDL cholesterol in these genes also lowers risk
[12:50] SPEAKER_02: of cardiovascular disease.
[12:53] SPEAKER_02: The same is true for LP little A,
[12:56] SPEAKER_02: as you mentioned, and the same exercise had also been done for interleukin-6.
[13:02] SPEAKER_02: On the other hand,
[13:03] SPEAKER_02: if we run the same exercise for C-reactive protein,
[13:07] SPEAKER_02: we find genetic variants within the gene coding CRP that influence CRP levels.
[13:13] SPEAKER_02: Those genetic variants do not show any association with the risk
[13:15] SPEAKER_02: of coronary artery disease or other cardiovascular disease endpoints.
[13:19] SPEAKER_02: And the same is true for HDL.
[13:21] SPEAKER_02: If we find variants that raise HDL but have no influence on LDL cholesterol,
[13:26] SPEAKER_02: they do not influence the risk of cardiovascular disease.
[13:29] SPEAKER_01: Well, that's what you just said is really important, okay?
[13:33] SPEAKER_01: Because even though we're going to talk about how HSCRP was used in these trials as
[13:39] SPEAKER_01: an entry criteria,
[13:40] SPEAKER_01: particularly in Zeus, and it hasn't been established that HSCRP is a causal factor.
[13:49] SPEAKER_01: No less the fact that anything can raise HSCRP.
[13:52] SPEAKER_01: You have a cold, you had a bump on your knee.
[13:56] SPEAKER_01: I mean, you know, anything can raise HSCRP.
[13:59] SPEAKER_01: No less chronic illness of many kinds.
[14:01] SPEAKER_01: So this is a real problem of using a nonspecific marker.
[14:05] SPEAKER_01: And of course, you know, you brought up the HDL story.
[14:07] SPEAKER_01: We saw how very high HDL can actually be associated with adverse outcomes.
[14:15] SPEAKER_01: Yeah, your explanation of that was really lucid.
[14:18] SPEAKER_01: Which is great.
[14:20] SPEAKER_01: But we're going to get further into that.
[14:22] SPEAKER_01: By the way, Karsten Schmidt has asked about oxidized phospholipid, OXPL.
[14:28] SPEAKER_01: We'll get into that because that may be especially important with respect to LpA,
[14:33] SPEAKER_01: the refined marker of what's actually the inflammatory trigger.
[14:40] SPEAKER_01: Okay, so we have this background.
[14:41] SPEAKER_01: LpA is causal, LDL is causal.
[14:46] SPEAKER_01: And even interleukin-6 has been shown causal.
[14:50] SPEAKER_01: The others, maybe not so much.
[14:52] SPEAKER_01: Now, enter Zeus.
[14:56] SPEAKER_01: We get this trial, 6,300-plus people.
[15:00] SPEAKER_01: And I was shocked because I didn't know what the entry criteria,
[15:03] SPEAKER_01: you had to have some chronic kidney disease and some prior heart disease,
[15:08] SPEAKER_01: high risk for heart disease, and an HSCRP of 2 or greater, 2 milligrams per kidney.
[15:16] SPEAKER_01: Can you comment about the entry criteria there?
[15:20] SPEAKER_02: Yes.
[15:20] SPEAKER_02: And we can, of course, go into the Mendelian randomization results.
[15:26] SPEAKER_02: Actually,
[15:27] SPEAKER_02: I believe we're very informative of designing the IntelliQ 6 or taking the decision
[15:34] SPEAKER_02: to bring the IntelliQ 6 hypothesis forward, because I think that's important.
[15:37] SPEAKER_02: But in terms of Zeus, so...
[15:40] SPEAKER_02: The inclusion criteria for Zeus were the patients needed to have evidence
[15:46] SPEAKER_02: of atherosclerotic cardiovascular disease,
[15:49] SPEAKER_02: chronic kidney disease,
[15:50] SPEAKER_02: as defined by GFR below 60, or high-sensitivity C-reactive protein above 2.
[15:57] SPEAKER_02: And this was, I assume, a controversial decision by Novo.
[16:08] SPEAKER_02: However, there were good reasons for that.
[16:10] SPEAKER_02: So number one was that we know patients with chronic kidney disease
[16:17] SPEAKER_02: to have higher seriactive protein levels.
[16:20] SPEAKER_02: This is a fact.
[16:22] SPEAKER_02: And we assume this to mean that they have higher levels of systemic inflammation.
[16:28] SPEAKER_02: Number two, we know that patients with chronic kidney disease have a higher cardiovascular risk.
[16:34] SPEAKER_02: And This is important because this is a risk that is potentially unaddressed
[16:41] SPEAKER_02: by modern pharmacotherapies,
[16:44] SPEAKER_02: but at the same time means that a trial can be completed probably faster
[16:50] SPEAKER_02: because those patients accumulate events in a shorter period of time.
[16:55] SPEAKER_02: And third,
[16:56] SPEAKER_02: I think at the time that Zeus was designed,
[16:59] SPEAKER_02: there was another anti-inflammatory drug that actually had succeeded
[17:03] SPEAKER_02: in two phase three studies, an old school drug called Colticin, which...
[17:12] SPEAKER_02: It's used with caution.
[17:13] SPEAKER_02: It's not really contraindicated,
[17:14] SPEAKER_02: but it's used with caution in patients with chronic kidney disease.
[17:17] SPEAKER_02: And so this probably represented,
[17:23] SPEAKER_02: was attractive because it represented a potential market with less competition
[17:29] SPEAKER_02: than what would be in patients without chronic kidney disease for
[17:32] SPEAKER_02: an anti-inflammatory drug.
[17:34] SPEAKER_02: So I think this was the rationale for the criteria.
[17:40] SPEAKER_02: But of course,
[17:40] SPEAKER_02: there are good reasons for somebody to think why this might not have been
[17:48] SPEAKER_02: the optimal population, for example.
[17:52] SPEAKER_02: While we know that those people have higher inflammation
[17:55] SPEAKER_02: and have higher cardiovascular risk,
[17:57] SPEAKER_02: it doesn't mean we have no evidence
[17:58] SPEAKER_02: that their higher cardiovascular risk is actually because of higher inflammation,
[18:02] SPEAKER_02: right?
[18:02] SPEAKER_02: So there is no reason to believe that.
[18:05] SPEAKER_02: And on the other hand,
[18:07] SPEAKER_02: if we assume that a higher level of CRP
[18:11] SPEAKER_02: above two milligrams per liter means higher inflammation in the general population
[18:17] SPEAKER_02: or higher vascular inflammation in the general population,
[18:19] SPEAKER_02: in patients with chronic kidney disease that
[18:22] SPEAKER_02: Whose baseline CRP levels are anyways higher.
[18:24] SPEAKER_02: We don't really know if this higher CRP value really represents higher inflammation.
[18:33] SPEAKER_02: All these are, of course, interesting considerations.
[18:36] SPEAKER_02: And Novo Beyond Zeus designed two additional trial programs.
[18:44] SPEAKER_02: One was in patients with Heart failure,
[18:47] SPEAKER_02: which was a heart failure with preceptive rejection fraction.
[18:51] SPEAKER_02: The Hermes and Athena trials that were also discontinued because of futility just
[18:58] SPEAKER_02: a couple of days ago.
[19:00] SPEAKER_02: And the third one was Artemis, which is in the population with acute myocardial infarction.
[19:05] SPEAKER_02: So I assume with subgroup analysis from Zeus,
[19:10] SPEAKER_02: but also with the full results from the next trials,
[19:14] SPEAKER_02: we're going to I have to say I find it hard to believe that this is really
[19:27] SPEAKER_02: a population issue,
[19:28] SPEAKER_02: although I always found the choice controversial because the final hazard ratio was,
[19:36] SPEAKER_02: which is the only thing we know from the trial, was 0.99.
[19:38] SPEAKER_02: So it's a really
[19:41] SPEAKER_02: A brutally null result and very difficult to assume that there were subgroups
[19:47] SPEAKER_02: within this population that might have shown any benefit.
[19:52] SPEAKER_01: Right.
[19:53] SPEAKER_01: Now, just to be clear on the background,
[19:56] SPEAKER_01: because you touched,
[19:57] SPEAKER_01: there had been five trials of coltazine,
[20:00] SPEAKER_01: randomized trials,
[20:02] SPEAKER_01: and they showed overall a pretty substantial reduction,
[20:05] SPEAKER_01: not just in heart attack, but also stroke.
[20:10] SPEAKER_01: And coltrazine is not exactly an ideal inflammatory drug, but it certainly has some in there.
[20:16] SPEAKER_01: And then there was the trial of the interleukin-1-beta antibody,
[20:22] SPEAKER_01: which cantos,
[20:24] SPEAKER_01: which did lower cardiovascular adverse events,
[20:28] SPEAKER_01: but it also increased serious infections.
[20:31] SPEAKER_01: And it never moved forward.
[20:32] SPEAKER_01: But it was another example of suppressing an inflammatory process and some better outcomes.
[20:39] SPEAKER_01: But we haven't yet seen,
[20:40] SPEAKER_01: you know,
[20:41] SPEAKER_01: the definitive anti-inflammatory drug like here,
[20:44] SPEAKER_01: an IL-6 blocker antibody,
[20:48] SPEAKER_01: which did achieve its goal of suppressing IL-6 as it did suppress CRP,
[20:56] SPEAKER_01: but no outcome improved.
[20:59] SPEAKER_01: So that was,
[21:00] SPEAKER_01: of course,
[21:02] SPEAKER_01: not—well,
[21:04] SPEAKER_01: I should say, by the way, it was an antisense oligonucleotide, not an antibody.
[21:10] SPEAKER_01: And there are other preparations that are targeting IL-6
[21:16] SPEAKER_01: that are different preparations, not just IL-6, but also IL-6 receptor.
[21:21] SPEAKER_01: Can you comment about these other drugs and whether
[21:23] SPEAKER_01: or not they're substantively different from the one that was used in Zeus?
[21:28] SPEAKER_02: Yes.
[21:30] SPEAKER_02: So I think we can take a step back and discuss a little bit the evidence base
[21:37] SPEAKER_02: for targeting IL-6 in the space of cardiovascular disease.
[21:40] SPEAKER_02: We mentioned Mendelian randomization,
[21:42] SPEAKER_02: but beyond Mendelian randomization,
[21:45] SPEAKER_02: so the The evidence base
[21:48] SPEAKER_02: before just supporting IL-6 signaling was actually pretty broad, right?
[21:52] SPEAKER_02: So we have animal studies suggesting that
[21:55] SPEAKER_02: if we target interleukin-6 signaling pharmacologically,
[21:59] SPEAKER_02: we see mouse models of atherosclerosis, we see reductions.
[22:03] SPEAKER_02: We had studies suggesting that IL-6 levels
[22:05] SPEAKER_02: within vulnerable histologically unstable plaques are higher.
[22:14] SPEAKER_02: We had evidence from epidemiological studies,
[22:16] SPEAKER_02: as we suggested,
[22:17] SPEAKER_02: interleukin-6 levels, higher levels were associated with higher cardiovascular risk.
[22:22] SPEAKER_02: We had secondary analysis from the Cantos trial that you already mentioned.
[22:25] SPEAKER_02: So the theory here is that IL-1 beta is upstream of interleukin-6,
[22:30] SPEAKER_02: and then CRP is the readout of this inflammatory mechanism.
[22:36] SPEAKER_02: So the theory says that interleukin-6 We inhibit interleukin 1 beta.
[22:41] SPEAKER_02: We lower L6.
[22:42] SPEAKER_02: And by doing so, we probably lower cardiovascular risk.
[22:45] SPEAKER_02: This was the theory before Zeus.
[22:47] SPEAKER_02: And in support of this theory,
[22:49] SPEAKER_02: secondary post-hook analysis from Kantos showed that the benefit you mentioned
[22:54] SPEAKER_02: for kanakinumab,
[22:55] SPEAKER_02: which was a 15% reduction in cardiovascular risk among patients with a history
[22:59] SPEAKER_02: of myocardial infarction,
[23:01] SPEAKER_02: was absolutely restricted to people For whom the antibody achieved the suppression
[23:08] SPEAKER_02: of IL-6.
[23:08] SPEAKER_02: So there's additional evidence.
[23:11] SPEAKER_02: But I believe the evidence that actually potentially moved the needle for people
[23:19] SPEAKER_02: to take the decision to invest in this program was probably the genetic evidence,
[23:25] SPEAKER_02: right?
[23:25] SPEAKER_02: And the genetic evidence originated from the receptor, not the ligand itself.
[23:29] SPEAKER_01: Well, that's key, right?
[23:30] SPEAKER_01: I mean, so...
[23:33] SPEAKER_01: The protein, the ligand, is indeed causal, but the receptor has better evidence.
[23:39] SPEAKER_02: So this is a very interesting area of genomic research.
[23:44] SPEAKER_02: So the genetic evidence for IL-6 receptor goes back to 2012,
[23:50] SPEAKER_02: where when two independent groups,
[23:53] SPEAKER_02: the results were published by both groups in the Lancet,
[23:57] SPEAKER_02: found two genetic variants within the IL-6 receptor gene.
[24:03] SPEAKER_02: That were associated with reductions in CRP to also be associated with reductions
[24:08] SPEAKER_02: in coronary artery disease risk.
[24:10] SPEAKER_02: And those variants we know nowadays,
[24:14] SPEAKER_02: they were both correlated because of this phenomenon of linkage disequilibrium.
[24:18] SPEAKER_02: We now assume one of the two to be the causal one.
[24:21] SPEAKER_02: And this variant is actually a variant within the coding region.
[24:26] SPEAKER_02: It turns a letter in the DNA,
[24:29] SPEAKER_02: an adenine to a cytosine,
[24:30] SPEAKER_02: which then means that An amino acid is being changed in the protein sequence
[24:36] SPEAKER_02: from aspartate to alanine.
[24:39] SPEAKER_02: And this is in the AL6 receptor.
[24:41] SPEAKER_02: And it causes the AL6 receptor that is usually bound to the membrane of cells
[24:49] SPEAKER_02: to be cleaved by proteases.
[24:52] SPEAKER_02: So to be...
[24:55] SPEAKER_02: To be subject to enhanced cleavage.
[24:58] SPEAKER_02: And by that,
[25:00] SPEAKER_02: we see reductions in downstream signaling as captured by reductions
[25:04] SPEAKER_02: in C-reactive protein.
[25:06] SPEAKER_02: And these reductions were translated also to reductions in risk of coronary artery disease.
[25:11] SPEAKER_02: So this was the original evidence.
[25:12] SPEAKER_02: And over the years,
[25:16] SPEAKER_02: my group and others were able to detect more variants in this gene
[25:20] SPEAKER_02: that are actually independent variants of the main one.
[25:23] SPEAKER_02: That actually also were associated with risk of cardiovascular disease in a kind of
[25:27] SPEAKER_02: a dose response pattern.
[25:29] SPEAKER_02: And this was the evidence for IL-6 receptor.
[25:33] SPEAKER_02: And until very recently, there was no evidence for interleukin-6.
[25:38] SPEAKER_02: Now, our own work later on,
[25:42] SPEAKER_02: that's a paper published last year in Nature Cardiovascular Research,
[25:47] SPEAKER_02: if We leverage modern genetic data sets.
[25:49] SPEAKER_02: We can actually also find genetic variants in the lopus of
[25:54] SPEAKER_02: the interleukin-6 ligand itself that are associated with lower expression.
[26:01] SPEAKER_02: Those are variants not in the coding region,
[26:03] SPEAKER_02: but in the non-coding region of the gene,
[26:05] SPEAKER_02: and they influence its expression within immune cells, particularly myeloid cells.
[26:11] SPEAKER_02: And those variants reduce L6 expression.
[26:14] SPEAKER_02: They reduce CRP as a result.
[26:17] SPEAKER_02: And they are also associated with a low risk
[26:18] SPEAKER_02: of cardiovascular coronary artery disease,
[26:20] SPEAKER_02: but also a spectrum of
[26:22] SPEAKER_00: atherosclerotic disease endpoints
[26:25] SPEAKER_02: from atherosclerotic stroke,
[26:28] SPEAKER_02: periparal artery disease, abdominal aneurysm, carotid atherosclerosis, all of that.
[26:33] SPEAKER_02: So I...
[26:37] SPEAKER_02: While I do believe that there might be differences in the biology of targeting IL-6
[26:41] SPEAKER_02: and IL-6 receptor,
[26:42] SPEAKER_02: I think that the main argument people use to support that IL-6 receptor would be
[26:47] SPEAKER_02: the right target was the genetic evidence.
[26:50] SPEAKER_02: But I do believe that there is also genetic evidence in the IL-6 itself.
[26:56] SPEAKER_00: The IL-6 ligand, the proteined causal.
[27:01] SPEAKER_00: Yes.
[27:01] SPEAKER_01: But that's good.
[27:02] SPEAKER_01: Because, you know, there are a bunch of other drugs out there.
[27:05] SPEAKER_01: They're much longer acting,
[27:07] SPEAKER_01: like small interfering RNA and other ways to get at this IL-6 story that we'll see
[27:15] SPEAKER_01: in the future.
[27:16] SPEAKER_01: But also the patient population may be important.
[27:20] SPEAKER_01: I would submit,
[27:21] SPEAKER_01: and I want to know what you think,
[27:22] SPEAKER_01: because,
[27:22] SPEAKER_01: you know,
[27:22] SPEAKER_01: I wrote a Substack on this too,
[27:24] SPEAKER_01: that if you measure systemic markers,
[27:27] SPEAKER_01: circulating blood markers,
[27:29] SPEAKER_01: they don't necessarily correlate at all with What's going on in
[27:33] SPEAKER_01: the coronary arteries.
[27:36] SPEAKER_01: And indeed,
[27:37] SPEAKER_01: at the Munich meetings of the ESC,
[27:40] SPEAKER_01: there was the FAI,
[27:45] SPEAKER_01: the Fat Attenuation Index Measurement,
[27:48] SPEAKER_01: a quantitative measure of coronary inflammation to the three coronaries.
[27:51] SPEAKER_01: It had terrible correlation with HSCRP.
[27:55] SPEAKER_01: I mean, our value was 0.2.
[27:56] SPEAKER_01: Okay.
[27:58] SPEAKER_01: So...
[27:59] SPEAKER_01: Blood doesn't necessarily mean what's going on in the artery.
[28:02] SPEAKER_01: Is that a fair conclusion?
[28:06] SPEAKER_02: I think that it absolutely is.
[28:10] SPEAKER_02: I think CRP has served its role in raising awareness about the idea
[28:16] SPEAKER_02: that inflammation is something that could be potentially measured,
[28:21] SPEAKER_02: that it is correlated with cardiovascular risk and future cardiovascular events.
[28:30] SPEAKER_02: It is a very nonspecific marker of inflammation and it is probably time
[28:38] SPEAKER_02: to start moving towards more specific biomarkers of vascular inflammation.
[28:41] SPEAKER_02: So similar to the data you mentioned about FAI,
[28:45] SPEAKER_02: I think the largest study today that tried to assess vascular inflammation was
[28:51] SPEAKER_02: the PESA study by Spanish investigators where they did PET MRI on the arteries
[29:00] SPEAKER_02: of I think over 700 people, carotids, aortas, femoral, FTG PET.
[29:06] SPEAKER_02: And we have some evidence from histopathological studies
[29:11] SPEAKER_02: that FTG uptake actually correlates with local plaque inflammation as quantified
[29:16] SPEAKER_02: by Macrophage content, right?
[29:17] SPEAKER_02: And I think in their paper,
[29:19] SPEAKER_02: they showed that if you try to correlate FTG uptake in the arteries with CRP,
[29:25] SPEAKER_02: you also see a correlation very similar to what you mentioned.
[29:29] SPEAKER_02: I think it was 0.24 around these lines.
[29:36] SPEAKER_02: And I believe also from the perspective of...
[29:41] SPEAKER_02: I mean, whoever has worked at the hospital knows how non-specific
[29:49] SPEAKER_02: elevations in therapy can be.
[29:51] SPEAKER_02: And so I agree with you that we could become wiser if we had good biomarkers
[30:01] SPEAKER_02: of local plaque inflammation.
[30:04] SPEAKER_00: Yeah, yeah.
[30:06] SPEAKER_01: Well, on those lines, yeah, of course.
[30:10] SPEAKER_01: There is an ongoing trial of an oxidized LDL antibody.
[30:15] SPEAKER_01: It's called OR2-Cumab, and it was also presented, some of the work at the recent ESC unit.
[30:24] SPEAKER_01: And they use the scan, FAI, the AI quantification, for an entry criteria.
[30:34] SPEAKER_01: Okay, so they are really going to the source,
[30:38] SPEAKER_01: the coronary inflammation, to test their antibody.
[30:42] SPEAKER_01: I don't know whether it'll work,
[30:43] SPEAKER_01: but I have to admire that they're using a very more specific tool
[30:47] SPEAKER_01: to identify patients who are included in the trial.
[30:50] SPEAKER_01: That's the first trial I know of that's zeroing in
[30:54] SPEAKER_01: on actual coronary inflammation rather than relying on a nonspecific blood marker,
[30:59] SPEAKER_01: whether or not that marker is identified as causal.
[31:03] SPEAKER_01: In fact, it was funny.
[31:05] SPEAKER_01: Just a few days before the Horizon trial came out on LP little A,
[31:10] SPEAKER_01: I had no idea it was coming out.
[31:12] SPEAKER_01: And I still don't know why it didn't come out in the days during the big ESC meeting.
[31:17] SPEAKER_01: Instead, it was waited for Friday evening.
[31:19] SPEAKER_01: But just a few days,
[31:21] SPEAKER_01: there was a paper showing the causality and the Mendelian randomization of LpLLA,
[31:26] SPEAKER_01: one of other studies that have done so, even in people who had LDL lowering, right?
[31:32] SPEAKER_01: So it isn't just that you can get all the bang just from LDL lowering,
[31:36] SPEAKER_01: it was even more with Targeting LPA.
[31:41] SPEAKER_01: So this is really fascinating.
[31:43] SPEAKER_01: And now we want to shift into Horizon.
[31:45] SPEAKER_01: But I do want to mention Aveda Nasri did also cite the prior work in Colchizine and Cantos.
[31:56] SPEAKER_01: So to give credit, as you mentioned, all those who have questions, we will try to get to them.
[32:02] SPEAKER_01: There was a question about other markers,
[32:07] SPEAKER_01: Low-grade inflammation and cardiovascular risk that Christian Jaggi has raised.
[32:12] SPEAKER_01: We'll get to that.
[32:14] SPEAKER_01: But now let's just switch gears.
[32:17] SPEAKER_01: Unless you want to go, something you were going to say, Marius?
[32:20] SPEAKER_02: No, I also wanted to add to what you mentioned,
[32:26] SPEAKER_02: Eric, about using such biomarkers for selecting the right patients.
[32:32] SPEAKER_02: But I think such biomarkers can also be useful for Assessing efficacy in principle, right?
[32:38] SPEAKER_02: So we now know,
[32:40] SPEAKER_02: we have quite a few trials to know that reductions in CRP,
[32:45] SPEAKER_02: although they might be correlated with reductions in cardiovascular risk,
[32:49] SPEAKER_02: this definitely doesn't seem to be the rule.
[32:52] SPEAKER_02: So in principle, We see, we have some trials.
[32:58] SPEAKER_02: We have the SEER trial testing, Methotrix 8.
[33:00] SPEAKER_02: We have the KANTOS trial testing, Kanakinumab.
[33:03] SPEAKER_02: We have some of the coaches in trials like CONVINCE and STROKE that measured CRP as well.
[33:08] SPEAKER_02: And now we have zoos that measured CRP.
[33:11] SPEAKER_02: And in principle,
[33:11] SPEAKER_02: we know that Changes in CRP actually do not perfectly correlate with changes
[33:15] SPEAKER_02: in cardiovascular risk.
[33:16] SPEAKER_02: So also because Zeus,
[33:18] SPEAKER_02: that actually achieved the largest reduction to date,
[33:22] SPEAKER_02: didn't translate to cardiovascular risk reduction.
[33:25] SPEAKER_02: And so I believe that such biomarkers could be useful also for assessing efficacy at
[33:33] SPEAKER_02: an earlier time point before taking the decision to invest in
[33:37] SPEAKER_02: a massive phase three clinical trial for Without having previously any evidence
[33:43] SPEAKER_02: of efficacy at the primary pathology level, which is the plaque.
[33:50] SPEAKER_01: You know,
[33:50] SPEAKER_01: you're making a really good point because these trials cost hundreds of millions
[33:54] SPEAKER_01: of dollars, maybe even a billion dollars.
[33:57] SPEAKER_01: Like, you know, Horizon 8,300 plus participants started in 2019.
[34:04] SPEAKER_01: So it went on seven years.
[34:05] SPEAKER_01: I mean, it may have cost, you know, upwards of a billion dollars to do this trial.
[34:09] SPEAKER_01: So talking about big Big shot to your big investment.
[34:13] SPEAKER_01: All right, so now Horizon is a different test.
[34:17] SPEAKER_01: It's testing the ability to lower LP little A.
[34:21] SPEAKER_01: We know LP little A is causal.
[34:24] SPEAKER_01: We know that, at least by Mendelian randomization that we reviewed.
[34:29] SPEAKER_01: But the real test was we didn't have a drug that was specific to LP little A.
[34:35] SPEAKER_01: And this was the first one.
[34:36] SPEAKER_01: It was a Novartis drug.
[34:38] SPEAKER_01: It was an antisense oligonucleotide.
[34:43] SPEAKER_01: Its criteria for entry for LP was not particularly a threshold for some of the other trials.
[34:53] SPEAKER_01: But nonetheless, it did a big test, and it was a bust.
[34:57] SPEAKER_01: We don't know the details, just like Zeus.
[34:59] SPEAKER_01: All we have are press releases, right?
[35:04] SPEAKER_01: This was not expected.
[35:06] SPEAKER_01: In fact,
[35:06] SPEAKER_01: you know,
[35:07] SPEAKER_01: I have many patients that in clinic,
[35:08] SPEAKER_01: they have very high LP,
[35:11] SPEAKER_01: and they're very worried that just because we lower the LDL aggressively,
[35:15] SPEAKER_01: is that enough?
[35:17] SPEAKER_01: They've been anticipating the availability of this drug in 2027.
[35:23] SPEAKER_01: And the other trials of the multiple programs that are out there,
[35:26] SPEAKER_01: they're not even going to be out till 2028 or 2029,
[35:31] SPEAKER_01: even though there are different types of drugs And different thresholds
[35:34] SPEAKER_01: and different patient populations, whatever.
[35:37] SPEAKER_01: So this was not anticipated,
[35:41] SPEAKER_01: unless you were thinking that LPLLA wasn't causal or
[35:45] SPEAKER_01: that there was something wrong here with the patient population.
[35:48] SPEAKER_01: How do you get to what went wrong in this trial?
[35:55] SPEAKER_02: Yeah, so I think that's, of course, a really half a billion dollar question, right?
[36:03] SPEAKER_02: And very,
[36:04] SPEAKER_02: very difficult,
[36:05] SPEAKER_02: very easy probably to make hypothesis retrospectively about what went wrong.
[36:09] SPEAKER_02: But of course,
[36:12] SPEAKER_02: I do believe that we should congratulate the trial teams
[36:18] SPEAKER_02: for running this massive Herculean effort.
[36:20] SPEAKER_00: Oh, yeah.
[36:22] SPEAKER_02: Absolutely.
[36:23] SPEAKER_02: And so I think here we're talking about a different approach.
[36:31] SPEAKER_02: So again,
[36:33] SPEAKER_02: lipoprotein little a,
[36:34] SPEAKER_02: there was very,
[36:35] SPEAKER_02: very strong evidence from human genetics supporting that it is associated,
[36:41] SPEAKER_02: that it might be potentially causal for atherosclerosis development.
[36:45] SPEAKER_02: So as opposed to interleukin-6 signaling,
[36:48] SPEAKER_02: which is only to a very small extent genetically determined,
[36:52] SPEAKER_02: LP levels are largely genetically determined.
[36:55] SPEAKER_02: So according to some studies, up to 90%.
[36:58] SPEAKER_02: And most of this
[37:03] SPEAKER_02: variation is originating at the gene coding for the protein itself,
[37:08] SPEAKER_02: apolipoprotein alpha.
[37:10] SPEAKER_02: And the
[37:13] SPEAKER_02: And there, again,
[37:16] SPEAKER_02: we have very strong evidence that each genetic variant
[37:19] SPEAKER_02: that influences LP levels influences risk of coronary artery disease in
[37:25] SPEAKER_02: a proportional way.
[37:26] SPEAKER_02: And so this raised confidence that this is probably a causal pathway for
[37:35] SPEAKER_02: I have to say that there are a lot of potential limitations in this.
[37:38] SPEAKER_02: We didn't come into that in this Mendelian randomization studies, right?
[37:41] SPEAKER_02: And potentially a lot of assumptions that need to be taken into account.
[37:45] SPEAKER_02: But both of those cases,
[37:48] SPEAKER_02: we're talking about very,
[37:50] SPEAKER_02: very, very, very strong and well reproducible evidence, right?
[37:56] SPEAKER_02: Similar to LDL,
[37:58] SPEAKER_02: it was the assumption that if we would lower LPDLA,
[38:03] SPEAKER_02: we would probably achieve reductions in cardiovascular risk.
[38:08] SPEAKER_02: Now, there are a number of important considerations here.
[38:12] SPEAKER_02: So genetics,
[38:15] SPEAKER_02: at its core,
[38:17] SPEAKER_02: what it tells us is about the lifetime of Exposure to differences in LP levels,
[38:24] SPEAKER_02: right?
[38:25] SPEAKER_02: And this is usually, we usually study populations in middle to late, to middle age to late life.
[38:34] SPEAKER_02: So it might be over 50 years, median age.
[38:37] SPEAKER_02: And those folks have been exposed to different LP levels throughout their lifetimes.
[38:42] SPEAKER_02: And then we go and intervene with a medication now in Horizon, for example, at
[38:51] SPEAKER_02: At midlife for a very short period of time.
[38:54] SPEAKER_02: And what I want to say is that the genetic evidence might not translate to this.
[39:03] SPEAKER_02: LPA versus a short term.
[39:08] SPEAKER_02: Actually, it's a very, very interesting case here because...
[39:15] SPEAKER_02: Steve Burgess and Brian Perens, I think it's a 2018 paper in Zama Cardiology.
[39:20] SPEAKER_02: They tried,
[39:20] SPEAKER_02: they took the LDL evidence and they said,
[39:22] SPEAKER_02: okay, for LDL, we know how LDL reduction with pharmacotherapies actually performs.
[39:32] SPEAKER_02: So we have studied it deeply across different baseline LDL levels,
[39:37] SPEAKER_02: across different settings,
[39:38] SPEAKER_02: and we know that if we lower LDL by Let's say around 40 milligrams per deciliter
[39:43] SPEAKER_02: for five years, we achieve reductions of 20 to 25% in cardiovascular risk.
[39:49] SPEAKER_02: And we know that if we then take the genetic variants that lower LDL levels,
[39:55] SPEAKER_02: we see a reduction over an average of 50,
[39:58] SPEAKER_02: 55 years,
[39:58] SPEAKER_02: let's say over a lifetime,
[40:00] SPEAKER_02: that corresponds to close 50% risk reduction for The same reduction in LBL,
[40:09] SPEAKER_02: but over the lifetime.
[40:10] SPEAKER_02: And they tried to use this process This ratio of,
[40:17] SPEAKER_02: let's say,
[40:17] SPEAKER_02: genetic to clinical reduction to translate what we would expect for the LP trials,
[40:25] SPEAKER_02: right?
[40:25] SPEAKER_02: And of course,
[40:26] SPEAKER_02: this carries a lot of assumptions because we have no evidence,
[40:29] SPEAKER_02: we don't really know how reducing LP is going to pursue.
[40:33] SPEAKER_02: But in their analysis,
[40:35] SPEAKER_02: assuming that the two would perform equal,
[40:39] SPEAKER_02: they found that We would need a 100 milligrams per deciliter reduction in LP little
[40:45] SPEAKER_02: A to achieve a risk reduction that would be comparable to what we see
[40:52] SPEAKER_02: with 40 milligrams per deciliter reduction in LDL cholesterol,
[40:57] SPEAKER_02: which would be 20 to 25% risk reduction.
[41:01] SPEAKER_02: And so if somebody sees now the inclusion criteria of Horizon,
[41:06] SPEAKER_02: we see that they selected the population of With LP levels
[41:11] SPEAKER_02: above 70 mg per deciliter.
[41:14] SPEAKER_02: I think the median was around 100, 108.
[41:15] SPEAKER_02: And given that the drug lowers LP by around 70-80% on the basis of the Phase II study.
[41:24] SPEAKER_02: So we are below this 100 mg per deciliter
[41:30] SPEAKER_02: average reduction.
[41:32] SPEAKER_02: And the trial was powered to detect a hazard ratio of around 0.8.
[41:36] SPEAKER_02: So what I want to say is that it's...
[41:41] SPEAKER_02: It was a trial at the...
[41:45] SPEAKER_02: What I want to say is that we should wait to see the final hazard ratio.
[41:48] SPEAKER_02: I think it's a different story than IntelliQ 6 because I believe it will be
[41:53] SPEAKER_02: a completely different interpretation if we see a hazard ratio of 0.86
[41:57] SPEAKER_02: that barely crossed 1 versus a hazard ratio of 1 that is entirely new, right?
[42:04] SPEAKER_02: Right.
[42:05] SPEAKER_01: A null effect versus at least going in the right direction.
[42:10] SPEAKER_01: Yeah, the magnitude as anticipated.
[42:13] SPEAKER_01: But also what you're alluding to here, Marius,
[42:16] SPEAKER_01: is that the drug,
[42:19] SPEAKER_01: even though it's a front-runner drug,
[42:21] SPEAKER_01: it's not as powerful as some of the other drugs.
[42:23] SPEAKER_01: I mean, there's siRNAs that are getting...
[42:29] SPEAKER_01: 99% reduction, not 70 to 80%.
[42:32] SPEAKER_01: And if you say the length of follow-up, you know, could be longer too.
[42:38] SPEAKER_01: And some of these are just given every three months or every six months
[42:41] SPEAKER_01: and potentially even every year, one shot, one sub-Q injection.
[42:46] SPEAKER_01: So there are lots more legs out there in this story of LP little A.
[42:52] SPEAKER_01: I hope one of the lessons that you're getting at will be that they extend
[42:55] SPEAKER_01: the follow-up.
[42:57] SPEAKER_01: You know, amend the protocol, extend the follow-up.
[43:00] SPEAKER_01: Of course, await for the details to come out of this Horizon LP little a first trial.
[43:06] SPEAKER_01: But it may not be as big a miss as you're getting at
[43:09] SPEAKER_01: than people are right now anticipating, right?
[43:14] SPEAKER_02: I believe we're going to learn much more from when we have the results of Horizon,
[43:17] SPEAKER_02: but also when we have the results of the future trials.
[43:19] SPEAKER_02: Because I think there are three ways of actually...
[43:25] SPEAKER_02: Getting to a potentially stronger effect if LP little a ends up really being causal, right?
[43:31] SPEAKER_02: So one is to go into populations with higher levels,
[43:35] SPEAKER_02: higher baseline levels of LP little a, and some of the coming trials do that.
[43:41] SPEAKER_02: The other way is to lower LP little a more aggressively.
[43:46] SPEAKER_02: The SI-RNAs versus the antisense oligonucleides do that.
[43:51] SPEAKER_02: As you said, they lower L-A by up to 97%, 98%, 99%.
[43:56] SPEAKER_02: And the third way is to,
[43:58] SPEAKER_02: as you said,
[43:59] SPEAKER_02: extend the follow-up and expose those people for longer periods of time
[44:03] SPEAKER_02: to lower ibuprofen L-A.
[44:08] SPEAKER_02: Yes.
[44:08] SPEAKER_02: So it's all...
[44:09] SPEAKER_02: So I think we're going to learn a lot from the coming trials,
[44:16] SPEAKER_02: and I think it's also going to be very interesting from a human genetics point
[44:22] SPEAKER_02: of view to get a deeper understanding
[44:26] SPEAKER_02: of how human genetic findings can be translated.
[44:29] SPEAKER_01: And, you know,
[44:31] SPEAKER_01: like a subgroup analysis may not have been planned since
[44:34] SPEAKER_01: the trial started seven years ago.
[44:38] SPEAKER_01: Is to look at those who were on the longest time versus shorter duration just to get
[44:43] SPEAKER_01: a sense about that.
[44:44] SPEAKER_01: No, you're bringing up a great point there.
[44:47] SPEAKER_01: So now let's get to this issue,
[44:50] SPEAKER_01: which is LP could be very high,
[44:55] SPEAKER_01: but not having much oxidized phospholipid containing the cargo that is
[45:01] SPEAKER_01: the pro-inflammatory cargo.
[45:04] SPEAKER_01: The levels don't necessarily...
[45:08] SPEAKER_01: Carly, with the potency of pro-inflammatory action.
[45:16] SPEAKER_01: Anything that, well,
[45:17] SPEAKER_01: we could measure oxidized phospholibid in people and see whether or not that is part
[45:22] SPEAKER_01: of the story.
[45:24] SPEAKER_01: Any thoughts about that?
[45:27] SPEAKER_02: Well, I believe that all those explanations are interesting and Are interesting
[45:36] SPEAKER_02: and potentially plausible.
[45:39] SPEAKER_02: I'm not aware whether oxidized phospholipids were quantified
[45:47] SPEAKER_02: in earlier phase two studies of the Leckerson, I have to admit.
[45:54] SPEAKER_01: But they have been in other studies and there wasn't such a,
[45:57] SPEAKER_01: like for example,
[45:58] SPEAKER_01: in studies of aortic stenosis,
[46:00] SPEAKER_01: which LPA does increase the risk and they were not You know, aligned.
[46:07] SPEAKER_01: And so, you know, you could get more insight about what's really going on.
[46:10] SPEAKER_01: So, as opposed to the Zeus trial,
[46:13] SPEAKER_01: where the issue was coronary versus blood,
[46:16] SPEAKER_01: here we're talking about within the LPA,
[46:19] SPEAKER_01: the molecule, how much of it was carrying the culprit.
[46:24] SPEAKER_01: Some people could have a high LPA level and may not really denote any substantial risk.
[46:30] SPEAKER_01: You know, that's a theory.
[46:32] SPEAKER_01: There's some data to back it up, but it needs more work anyway.
[46:37] SPEAKER_01: That's something I'm thinking about, but we'll see.
[46:41] SPEAKER_01: But now the story here is we want people with coronary inflammation.
[46:46] SPEAKER_01: We want active coronary inflammation.
[46:49] SPEAKER_01: So if you can get a CT scan for $100,
[46:53] SPEAKER_01: low resolution,
[46:54] SPEAKER_01: and you could quantify the inflammation in each artery,
[46:59] SPEAKER_01: So forget the calcium score, which can be very misleading.
[47:03] SPEAKER_01: People with zero calcium score can have very high extent of carnal inflammation in all arteries.
[47:09] SPEAKER_01: We've seen that.
[47:10] SPEAKER_01: So the question is,
[47:12] SPEAKER_01: do we do the future trials when we're trying to change lipids
[47:16] SPEAKER_01: and change inflammation mediators?
[47:20] SPEAKER_01: Should we be sure that we're getting the right patients in for,
[47:25] SPEAKER_01: you know, like that trial I mentioned that's doing that?
[47:28] SPEAKER_01: Will that make the trial smarter in terms of really going after the target
[47:32] SPEAKER_01: of coronary artery inflammation?
[47:34] SPEAKER_01: What do you think?
[47:37] SPEAKER_02: Well, I do believe that especially when it comes to entirely novel hypotheses
[47:44] SPEAKER_02: where we don't have previous evidence of efficacy.
[47:47] SPEAKER_02: Because if we talk about LDL cholesterol lowering, I think...
[47:51] SPEAKER_02: There is very substantial evidence that LDL cholesterol is a great surrogate
[47:55] SPEAKER_02: of cardiovascular risk and even appreciated by the FDA that allows approval just on
[48:01] SPEAKER_02: the basis of LDL reduction.
[48:04] SPEAKER_02: But when it comes to entirely novel hypotheses like novel inflammatory target
[48:11] SPEAKER_02: or novel targets related to other mechanisms of plaque biology,
[48:19] SPEAKER_02: there I think that it will be inevitable to not move
[48:27] SPEAKER_02: towards more sophisticated study designs that include more sophisticated assessment
[48:32] SPEAKER_02: of plaque biology,
[48:36] SPEAKER_02: plaque morphology, and some kind of assessment of the primary pathology.
[48:42] SPEAKER_02: I still believe that We have to be pragmatic.
[48:46] SPEAKER_02: I don't believe that
[48:47] SPEAKER_02: a Phase III cardiovascular outcomes trial can really incorporate such kind
[48:50] SPEAKER_02: of imaging markers.
[48:53] SPEAKER_02: Well, you know, I'm not talking about an angiography.
[48:57] SPEAKER_02: But the Phase II study to assess efficacy or to provide proof of concept so that we
[49:05] SPEAKER_02: then move on in a Phase III study with higher confidence.
[49:07] SPEAKER_02: I think that this could be...
[49:12] SPEAKER_02: This would be reasonable, yes.
[49:13] SPEAKER_02: And I think that this would be the direction to go.
[49:17] SPEAKER_01: Yeah, I think, well, we disagree a little bit.
[49:19] SPEAKER_01: I think you're right about phase two would be easy,
[49:21] SPEAKER_01: but getting a CT, fast CT is a couple of minutes.
[49:25] SPEAKER_01: It's, you know, very low cost and it could be done anywhere.
[49:28] SPEAKER_01: I mean, it's all over.
[49:30] SPEAKER_01: It's being marketed for catharsis like it's, you know, sliced bread or something.
[49:36] SPEAKER_01: All right.
[49:38] SPEAKER_01: Now, one of the theories is Look, you just maxed out in cardiovascular disease.
[49:45] SPEAKER_01: In fact,
[49:45] SPEAKER_01: years ago,
[49:46] SPEAKER_01: the companies were all saying we're not even going to study it anymore because,
[49:49] SPEAKER_01: you know, we got the control group with all their drugs to lower LDL.
[49:54] SPEAKER_01: There's not much else we can do.
[49:57] SPEAKER_01: And then they came back to it with these recent interventions, IL-6 and LPLA.
[50:03] SPEAKER_01: But they were a bust so far.
[50:06] SPEAKER_01: And some people say, well, look, you just maxed out.
[50:09] SPEAKER_01: You just can't do any better.
[50:11] SPEAKER_01: Your thoughts?
[50:14] SPEAKER_02: Yes.
[50:15] SPEAKER_02: Actually,
[50:17] SPEAKER_02: in the Substack post you mentioned,
[50:19] SPEAKER_02: this was one of my potential explanations for why ISIS failed as well, right?
[50:25] SPEAKER_02: That inflammation was the wrong target altogether, that we should never go after inflammation.
[50:32] SPEAKER_02: And I think the main argument there of the people supporting that is not
[50:36] SPEAKER_02: that inflammation doesn't play a role in cardiovascular disease.
[50:39] SPEAKER_02: I think this is appreciated by most of the people in the community,
[50:43] SPEAKER_02: but that inflammation is so downstream of systemic vascular risk factors
[50:48] SPEAKER_02: that we are anyways treating very well and very aggressively,
[50:53] SPEAKER_02: that there isn't any more benefits to extract from doing that.
[50:59] SPEAKER_02: And...
[51:02] SPEAKER_02: I think it is a reasonable argument,
[51:04] SPEAKER_02: but on the other hand,
[51:06] SPEAKER_02: cardiovascular disease remains the leading cause of death worldwide.
[51:09] SPEAKER_02: And even if we see these two trials,
[51:11] SPEAKER_02: right, I mean, in both trials, there was residual cardiovascular risk.
[51:16] SPEAKER_02: I mean, the patients were in modern pharmacotherapies.
[51:20] SPEAKER_02: I think in Horizon, average LDL was 65, if I'm not mistaken, at baseline.
[51:28] SPEAKER_02: And still,
[51:29] SPEAKER_02: Over the trial duration,
[51:30] SPEAKER_02: median four or five years, more than 10% developed new cardiovascular events.
[51:37] SPEAKER_02: So there is still some unmet need there.
[51:42] SPEAKER_02: And so I believe there is still some space for improving our efforts.
[51:49] SPEAKER_02: And on the other hand,
[51:51] SPEAKER_02: I find it hard to come in terms with the idea that The only way to treat
[52:00] SPEAKER_02: the number one pathology causing the number one pathology,
[52:03] SPEAKER_02: the number one cause of death is by treating systemic vascular risk factors
[52:09] SPEAKER_02: and not going down to the primary, to the primary pathology, right?
[52:11] SPEAKER_02: So there has been decades of research into plaque biology,
[52:17] SPEAKER_02: local mechanisms driving plaque destabilization and plaque erosion,
[52:22] SPEAKER_02: plaque rupture, and, uh, uh,
[52:26] SPEAKER_02: At the moment,
[52:27] SPEAKER_02: all the pharmacotherapies we have act rather systemically rather than at
[52:31] SPEAKER_02: the plaque microenvironment.
[52:33] SPEAKER_02: And so I believe there is a very large body of research there that would be...
[52:42] SPEAKER_01: Well,
[52:45] SPEAKER_01: since you're big into genomics,
[52:48] SPEAKER_01: polygenic risk score for car disease is the most validated of all
[52:53] SPEAKER_01: the polygenic risk scores.
[52:55] SPEAKER_01: But there's a little problem, okay?
[52:57] SPEAKER_01: The little problem is, okay,
[52:59] SPEAKER_01: let's say you have a very high polygenic risk score in the top 1% for heart disease.
[53:05] SPEAKER_01: It doesn't tell you when.
[53:06] SPEAKER_01: It just tells you it could be at age 99 or it could be age 50, okay?
[53:12] SPEAKER_01: So what I'm getting at is we want to know the status of that person at a moment
[53:16] SPEAKER_01: in time, whether their arteries are inflamed.
[53:19] SPEAKER_01: And I don't think we're going to be able to really understand You know,
[53:22] SPEAKER_01: crack the ceiling here of max therapy.
[53:24] SPEAKER_01: And by the way, 65 LDL?
[53:27] SPEAKER_01: No, we can get it down to 10 or 20 if we really want to.
[53:32] SPEAKER_01: But the point is we're doing that now and people who don't need to have that done.
[53:36] SPEAKER_01: All right.
[53:37] SPEAKER_01: We got all these people that,
[53:38] SPEAKER_01: you know, have,
[53:40] SPEAKER_01: you know,
[53:40] SPEAKER_01: look at TikTok or Instagram or,
[53:42] SPEAKER_01: you know, whatever stuff that doesn't have good evidence.
[53:45] SPEAKER_01: And they say, I want to get my LDL down to, you know, zero.
[53:49] SPEAKER_01: And of course, they don't really need to do that.
[53:51] SPEAKER_01: And they're taking a lot of drugs to do that.
[53:53] SPEAKER_01: And we don't know whether it's benefiting them, okay?
[53:57] SPEAKER_01: So the point here is, and maybe it is, maybe it is.
[54:00] SPEAKER_01: But I want to know if I'm going to go after somebody
[54:04] SPEAKER_01: who doesn't have clear-cut risk,
[54:06] SPEAKER_01: and especially if I'm going to invest $500 million or a billion dollars,
[54:11] SPEAKER_01: I want to know they actually are at risk.
[54:14] SPEAKER_01: What better way do we have to know they're at risk?
[54:18] SPEAKER_02: And you saw,
[54:19] SPEAKER_02: I'm sure,
[54:21] SPEAKER_02: the recent study that was presented at the EEC last week,
[54:25] SPEAKER_02: but also published at the same time in the New England Journal of Medicine,
[54:28] SPEAKER_02: the REACT study from Denmark, pain, right?
[54:33] SPEAKER_02: Assessment of atherosclerosis with Stimble technology principle,
[54:40] SPEAKER_02: showing that after the age of 60,
[54:43] SPEAKER_02: almost everybody has some level of atherosclerosis.
[54:46] SPEAKER_02: But until then, there are real differences in the trajectories.
[54:51] SPEAKER_02: And what I found very fascinating as somebody being more
[54:54] SPEAKER_02: into cerebrovascular disease was that the proportion of people actually...
[55:02] SPEAKER_02: Having isolated coronary atheroscleros.
[55:04] SPEAKER_02: So they assessed,
[55:05] SPEAKER_02: this is a study where they assessed in 16,000 people
[55:08] SPEAKER_02: with ultrasound carotid arteries and femoral arteries and with coronary CTA,
[55:13] SPEAKER_02: their coronary arteries in the general population,
[55:16] SPEAKER_02: 16,000 people from 18 all the way up to, I think, 80 years.
[55:20] SPEAKER_02: And provided for the first time a picture of, Atherosclerosis burden across the lifetime.
[55:27] SPEAKER_02: But what I found very fascinating is that the proportion of people
[55:29] SPEAKER_02: who had isolated coronary atherosclerosis was actually very low.
[55:33] SPEAKER_02: It was less than 10% of the population.
[55:37] SPEAKER_02: Beyond coronary CTA, we have actually tools.
[55:41] SPEAKER_02: Ultrasound is extremely safe, radiation-free, very easy to do at any outpatient clinic setting.
[55:50] SPEAKER_02: And...
[55:52] SPEAKER_02: It's readily available in principle,
[55:54] SPEAKER_02: and we can use that to actually screen people who develop atherosclerosis,
[55:59] SPEAKER_02: monitor them over time to see how this develops.
[56:06] SPEAKER_01: Yeah, I agree.
[56:07] SPEAKER_01: You can look at plaque.
[56:09] SPEAKER_01: The problem is it's kind of like cancer.
[56:13] SPEAKER_01: You don't die from your tumor.
[56:15] SPEAKER_01: You die from metastasis.
[56:16] SPEAKER_01: In atherosclerotic disease, you don't die from plaque.
[56:19] SPEAKER_01: You die from plaque ruptured.
[56:22] SPEAKER_01: And fissure and erosion to cause heart attacks and sudden deaths.
[56:26] SPEAKER_01: So the point is plaque itself isn't enough.
[56:29] SPEAKER_01: You need to know it's really high risk plaque, high risk person, right?
[56:33] SPEAKER_01: So I don't know that plaque alone by ultrasound is going to, I do agree with you.
[56:38] SPEAKER_01: That's a very important study.
[56:41] SPEAKER_01: And by the way,
[56:43] SPEAKER_01: other studies have shown very young people,
[56:46] SPEAKER_01: even teens, can have significant plaque, no less 20s and 30s.
[56:51] SPEAKER_01: But the question is, is that plaque going to cause trouble in any given individual?
[56:56] SPEAKER_01: And I don't know that plaque burden enough.
[56:59] SPEAKER_01: Is that enough, right?
[57:02] SPEAKER_01: I mean, can we do better than these nonspecific markers,
[57:06] SPEAKER_01: lipoproteins that are not yet shown that you suppress them and change its event,
[57:11] SPEAKER_01: or just plaque itself?
[57:13] SPEAKER_01: Yeah.
[57:15] SPEAKER_02: Well, I do believe that at 30 stages, it's going to be hard to assess inflammation.
[57:22] SPEAKER_02: And on the other hand,
[57:25] SPEAKER_02: the The current status quo is actually assessing just risk factors, right?
[57:30] SPEAKER_02: So we assess age, sex,
[57:32] SPEAKER_02: and some basic risk factors with the different equations that exist at
[57:36] SPEAKER_02: the primary prevention setting, I mean.
[57:40] SPEAKER_02: Score two here in Europe,
[57:42] SPEAKER_02: prevent in the U.S.
[57:44] SPEAKER_02: And those definitely are very valid predicting who is having atherosclerosis and
[57:53] SPEAKER_02: who doesn't have atherosclerosis.
[57:54] SPEAKER_00: Yeah, yeah.
[57:56] SPEAKER_02: And so I believe there is a lot of space if we move towards primary prevention
[58:01] SPEAKER_02: to start to
[58:07] SPEAKER_02: lower risk at the population level.
[58:10] SPEAKER_01: I want to prevent the plaque from accumulating in the first place.
[58:14] SPEAKER_01: Don't misunderstand my assertion here.
[58:16] SPEAKER_01: I'm just saying that once it's there, it may not be so vulnerable, such a liability.
[58:25] SPEAKER_01: As if we could just know that that person has the real potential to have a plaque event, right?
[58:32] SPEAKER_01: Okay, this has been great.
[58:34] SPEAKER_01: We've gone just about an hour here.
[58:37] SPEAKER_01: I do want to open it up before we close if there's any further questions.
[58:40] SPEAKER_01: I've only picked up a few along the way.
[58:45] SPEAKER_01: So if you have any other questions before I say we're done with Marios, who is just a gem and...
[58:53] SPEAKER_01: It's fun to compare our views,
[58:56] SPEAKER_01: and we don't agree on everything,
[58:57] SPEAKER_01: but you also have some really excellent insights here,
[59:01] SPEAKER_01: and I think everyone can appreciate that.
[59:05] SPEAKER_01: Any other questions?
[59:07] SPEAKER_01: Did I miss anything that you want to bring up, Marius?
[59:11] SPEAKER_02: No, Eric, thanks a lot.
[59:14] SPEAKER_02: It was a real pleasure.
[59:17] SPEAKER_02: I think...
[59:20] SPEAKER_02: If anything,
[59:21] SPEAKER_02: what I would like to highlight is because this probably took
[59:29] SPEAKER_02: a lot of attention in
[59:31] SPEAKER_02: the last weeks with Horizon and Zeus is the whole idea that we can use genetics
[59:36] SPEAKER_02: to identify drug targets, right?
[59:40] SPEAKER_02: And I think we are
[59:44] SPEAKER_02: We went through a phase where this was hyped a lot as a concept.
[59:49] SPEAKER_02: We went through a phase where it matured into the concept that,
[59:54] SPEAKER_02: yeah, it might work sometimes, it might not work sometimes.
[59:57] SPEAKER_02: And now we are going through a phase where we have two Trials largely based
[1:00:02] SPEAKER_02: on human... whose ideas originated in human genetics failing.
[1:00:10] SPEAKER_02: And I just want to highlight here that I still strongly believe
[1:00:17] SPEAKER_02: that human genetics can point to causal biology.
[1:00:22] SPEAKER_02: I don't believe we have any better...
[1:00:26] SPEAKER_02: To, at the moment,
[1:00:28] SPEAKER_02: to identify mechanisms that are causally involved in
[1:00:37] SPEAKER_02: the pathogenesis
[1:00:38] SPEAKER_02: of human disease.
[1:00:41] SPEAKER_02: But on the other hand,
[1:00:42] SPEAKER_02: we have to remember that the fact that we lower with the risk biology doesn't mean
[1:00:48] SPEAKER_02: that we, the risk clinical translation, clinical development, those
[1:00:57] SPEAKER_02: Those are different arts and different.
[1:00:59] SPEAKER_02: They have their own nuances.
[1:01:04] SPEAKER_02: But we shouldn't forget the value.
[1:01:10] SPEAKER_01: I'm with you.
[1:01:10] SPEAKER_01: I'm with you on that.
[1:01:11] SPEAKER_01: Now, there's a couple of questions before we wrap up.
[1:01:14] SPEAKER_01: Flip asks,
[1:01:16] SPEAKER_01: does a focus on inflammation mean that teristo would be more valuable for screening
[1:01:21] SPEAKER_01: than clearly?
[1:01:23] SPEAKER_01: Just to be clear...
[1:01:25] SPEAKER_01: Clearly,
[1:01:25] SPEAKER_01: Elucid and Heart Flow are competitive technologies for assessing coronary artery,
[1:01:32] SPEAKER_01: but they don't look at inflammation.
[1:01:34] SPEAKER_01: Caristo has FDA for exclusive inflammation indication.
[1:01:39] SPEAKER_01: The others are looking at plaque burden, vulnerable plaque, abnormal flow, reserve.
[1:01:46] SPEAKER_01: So that's a big question,
[1:01:47] SPEAKER_01: of course,
[1:01:48] SPEAKER_01: now that you could do a Caristo in the future without even having to do CT angio.
[1:01:54] SPEAKER_01: I don't know your thoughts.
[1:01:57] SPEAKER_02: I mean, I'm...
[1:01:59] SPEAKER_02: I believe those technologies,
[1:02:01] SPEAKER_02: because they move,
[1:02:02] SPEAKER_02: as we discussed,
[1:02:03] SPEAKER_02: towards assessing plaque presence and morphology directly and different features
[1:02:09] SPEAKER_02: of plaque biology, I think...
[1:02:12] SPEAKER_02: There is a lot of promise there,
[1:02:13] SPEAKER_02: but I also do believe that we still need,
[1:02:16] SPEAKER_02: I would like to see those technologies implemented in the context of clinical trials
[1:02:19] SPEAKER_02: so that to see their value in real decision-making situations.
[1:02:30] SPEAKER_02: And yes, so this would be my answer.
[1:02:34] SPEAKER_01: Yeah, I mean,
[1:02:35] SPEAKER_01: only a couple have been validated with histology in arteries and And Caristo was,
[1:02:43] SPEAKER_01: you know, eminently validated.
[1:02:46] SPEAKER_01: And I mean, I think that's what a real dilemma right now.
[1:02:49] SPEAKER_01: But of course, what I wrote about was I thought that that technology has a lot of potential.
[1:02:55] SPEAKER_01: Now, Ryan O'Young wrote a question.
[1:02:58] SPEAKER_01: What can we learn about the discrepancies between Mendelian randomization and the trials?
[1:03:03] SPEAKER_01: Or would there be additional things we have to consider from now on?
[1:03:07] SPEAKER_01: You touched on that, but maybe you can amplify it.
[1:03:11] SPEAKER_02: Yes, I do believe that considering the clinical context is important
[1:03:16] SPEAKER_02: because genetics does not really inform us about that.
[1:03:20] SPEAKER_02: I think there are two... One critical example probably here, I think, is factor 11, the...
[1:03:31] SPEAKER_02: The target,
[1:03:32] SPEAKER_02: so very recently,
[1:03:33] SPEAKER_02: asyndexion gained sodeficacy in lowering non-cardioembolic stroke
[1:03:38] SPEAKER_02: and recurrent stroke in patients with a history of non-cardioembolic stroke.
[1:03:43] SPEAKER_02: And asyndexion is a small molecule inhibitor of factor 11.
[1:03:47] SPEAKER_02: And there was strong genetic evidence for factor 11 being involved
[1:03:50] SPEAKER_02: in Factor 11 variation being associated with the risk of ischemic stroke.
[1:03:56] SPEAKER_02: And it's a very interesting example
[1:03:57] SPEAKER_02: because actually variation was most strongly associated with cardiombolic stroke.
[1:04:02] SPEAKER_02: Although there was a strong signal also for non-cardiombolic stroke.
[1:04:05] SPEAKER_02: But when asin-dexin was tested in Atrial fibrillation patients
[1:04:10] SPEAKER_02: against modern anticoagulants, Apixaban, Rivaroxaban, and so on.
[1:04:14] SPEAKER_02: It failed to show efficacy.
[1:04:15] SPEAKER_02: The study stopped early.
[1:04:17] SPEAKER_02: It was discontinued because actually the drug performed worse than modern anticoagulants.
[1:04:23] SPEAKER_02: And so, of course, a genetic study could never give you such evidence.
[1:04:29] SPEAKER_02: A comparative analysis against the current clinical context and the fact
[1:04:34] SPEAKER_02: that atrial fibrillation patients are actually being already treated with
[1:04:37] SPEAKER_02: a very good drug.
[1:04:39] SPEAKER_02: But then moving on,
[1:04:40] SPEAKER_02: the drug showed efficacy in non-cardiobolic stroke where we didn't have such a...
[1:04:46] SPEAKER_02: where the signal was interestingly less strong, but at the same time...
[1:04:53] SPEAKER_02: Probably the clinical context was cleaner.
[1:04:55] SPEAKER_02: So what I want to say,
[1:04:56] SPEAKER_02: I think it's always important to take the clinical context and the clinical scenario
[1:05:00] SPEAKER_02: in which a drug might be used into account when trying to interpret
[1:05:07] SPEAKER_02: the genetic findings.
[1:05:09] SPEAKER_01: Right.
[1:05:10] SPEAKER_01: Well, I mean,
[1:05:10] SPEAKER_01: along those lines,
[1:05:11] SPEAKER_01: you know,
[1:05:12] SPEAKER_01: the question is now that we have 20%
[1:05:15] SPEAKER_01: of people have significantly elevated LPA levels,
[1:05:21] SPEAKER_01: And we don't have a specific drug.
[1:05:23] SPEAKER_01: We may never have a specific drug.
[1:05:25] SPEAKER_01: I hope we will.
[1:05:26] SPEAKER_01: But what do we do in the meantime?
[1:05:28] SPEAKER_01: And I think, yes,
[1:05:30] SPEAKER_01: you could just get everybody's people with LP little a get their LDL down to 20.
[1:05:35] SPEAKER_01: You could do that.
[1:05:36] SPEAKER_01: I mean, theoretically,
[1:05:37] SPEAKER_01: as long as they don't have some FH or other reasons to,
[1:05:41] SPEAKER_01: you know, that it's too hard to suppress.
[1:05:43] SPEAKER_01: But should you?
[1:05:45] SPEAKER_01: You know, should you?
[1:05:46] SPEAKER_01: Because, you know, it could be expensive with these PCSK9.
[1:05:50] SPEAKER_01: Now we have an oral blocker of that, which looks pretty good too.
[1:05:53] SPEAKER_01: But nonetheless, these are not necessarily covered by insurance.
[1:05:56] SPEAKER_01: And it could be a big issue.
[1:05:58] SPEAKER_01: They have side effects.
[1:06:00] SPEAKER_01: Certainly statins have side effects.
[1:06:01] SPEAKER_01: So that is a question now.
[1:06:04] SPEAKER_01: And I don't know how to answer that.
[1:06:07] SPEAKER_01: Except, you know, yeah,
[1:06:08] SPEAKER_01: get everybody LDL down to 20 or see if they have inflammation,
[1:06:14] SPEAKER_01: coronary inflammation.
[1:06:16] SPEAKER_01: That to me needs to be assessed prospectively because maybe we don't have to push this.
[1:06:22] SPEAKER_01: We're going to be waiting for years now for people who have a very high LP little
[1:06:27] SPEAKER_01: A level and are hand-waving.
[1:06:30] SPEAKER_01: And, you know, a lot of physicians, cardiologists are going to just go to the max reduction.
[1:06:36] SPEAKER_01: But maybe that's not necessary in all these folks.
[1:06:40] SPEAKER_01: Maybe we should measure oxidized phospholipids or other means to determine.
[1:06:45] SPEAKER_01: And by the way,
[1:06:46] SPEAKER_01: if you do get the LDL down to very low levels and it's over six months or a year,
[1:06:53] SPEAKER_01: what if there's still persistent inflammation?
[1:06:56] SPEAKER_01: You know, this could be a very high risk patient.
[1:06:58] SPEAKER_01: So anyway, I just leave that dangling because we don't know, right?
[1:07:05] SPEAKER_02: I agree with you, Eric.
[1:07:06] SPEAKER_02: I think the main answer is we don't know.
[1:07:08] SPEAKER_02: We have to wait for the future trials and hope we will be wiser in a few years.
[1:07:14] SPEAKER_01: Yeah, I hope so too.
[1:07:15] SPEAKER_01: Well, you've made us wiser today, Mario.
[1:07:18] SPEAKER_01: So thank you for joining.
[1:07:20] SPEAKER_01: I also want to thank all the 400 plus folks who have joined us today.
[1:07:24] SPEAKER_01: It's been a fun discussion.
[1:07:25] SPEAKER_01: I've learned a lot.
[1:07:26] SPEAKER_01: Hopefully you have as well.
[1:07:28] SPEAKER_01: We've gotten to a lot of issues about current disease, the number one killer of man.
[1:07:35] SPEAKER_01: And hopefully we're going to do better in the future and that we're not maxed out.
[1:07:39] SPEAKER_01: Let's hope we're not, because I think there's lots of room for improved All right.
[1:07:44] SPEAKER_01: Well, thank you.
[1:07:45] SPEAKER_00: Take care.
[1:07:46] SPEAKER_02: Real pleasure.
[1:07:48] SPEAKER_00: Same here.
[1:07:49] SPEAKER_00: Thanks.
[1:07:49] SPEAKER_00: Bye-bye now.

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