The End of Heart Disease in a SINGLE Dose?

[00:00:00]Something just released that has the greatest potential to drastically and even potentially eliminate atherosclerotic cardiovascular disease.

[00:00:10]The effects are dramatic. The convenience is undeniable and all of it is pretty scary. I'm talking about the new Verve 102 trial that just released.

[00:00:22]So let's talk about where we are with the evidence, what it does, and the potential implications.

[00:00:28]In cardiology, it's well accepted that the cholesterol containing lipoproteins that are found in your blood are a causal factor in atheroscllerotic cardiovascular disease. To touch on that a bit, we're talking about the plaque buildup within your arteries. The idea which has been around for decades is that these cholesterol-containing lipoproteins if they're too abundant can get retained within the artery wall at a higher degree than they're able to escape. These lipoproteins also get damaged or oxidized which leads to an inflammatory response and the process accelerates. In late stages where a significant amount of plaque has built up within the arteries, the softest versions of this plaque can break and get lodged in the finer vessels leading to starvation of the tissue downstream of that blockage leading to tissue death. Obviously, if we're talking about the brain or the heart, that can be lethal. So over the last many decades, scientists and medical practitioners have discovered and designed a variety of different treatments from statin therapies to PCSK9 inhibitors to reduce the number of these cholesterol containing lipoproteins in the blood.

[00:01:39]The rationale is that if you reduce the number of these lipoprotein particles enough, then you can either slow or stop or in some instances reverse the plaque buildup within the arteries that has already presented itself. Those kinds of ideas come out partly, although not completely, from studies like the Pisa study. In this study, a little over 4,000 people without known cardiovascular disease or any other chronic illness had multiple non-invasive images taken of a variety of blood vessels to identify the relationship between these lipoproteins and the plaque buildup in our arteries like we just discussed. So, over the next few years, these people had their blood vessel plaque tracked and we can see those results. Here we have different buckets for the ranges of these cholesterol containing lipoproteins. On the horizontal axis, it's measured as an LDLC or low density lipoprotein cholesterol. The vertical axis is split in two with a description of no plaque buildup or plaque buildup.

[00:02:36]The higher the bars go from the starting point of zero, the more plaque is built up in the blood vessels. If the bars go down from zero, like the purple bars that we see here, there is no plaque in the arteries. Generally, you'll notice there's an association with greater cholesterol containing lipoprotein burden and more plaque buildup in the arteries. On the opposite side of the same coin, having a low burden of these cholesterol containing lipoproteins tends to yield little to no plaque growth. There are certainly limitations to studies like this. For example, while they did include 4,000 participants, the sample of the number of participants included in some of the groups was tiny.

[00:03:14]So, should we be basing our conclusions off the group sizes of two people?

[00:03:20]Obviously not. Still, it's not like this is the only evidence that's put forward.

[00:03:25]And we're talking about people that have not been diagnosed with cardiovascular disease. We can see a sizable relationship between lipoprotein burden and plaque. This is after adjusting for a number of other factors. Still, like I said, it's not the only evidence put forward, and I'm not here to discuss every shred of evidence on the topic. I think one more important study that I should mention is the Mandelian randomization trials. In very brief terms, people are split by specific genes that have been identified to drop cholesterol containing lipoproteins for the entirety of a person's life. So we can then compare the people that have these mutations that provide extremely low lipoprotein levels to people who do not have these mutations, which is the majority of the population. And then since we're reasonably sure that the effect is only on cholesterol containing lipoproteins, we can look at the cardiovascular outcomes to tease out if there are any benefits. Now, I suppose it won't shock you when I tell you that these studies show a significant reduction in cardiovascular disease risk in people with these protective mutations. This is especially powerful evidence because it has multiple strengths that can't be replicated in randomized control trials or even epidemiological studies because they combine both strengths in one. So the point I'm making here is that there's evidence and it goes far beyond what we just covered. Lowering cholesterol containing lipoproteins provides an immense benefit in reducing the risk of atheroscerotic or plaquereated cardiovascular disease. This is why we've developed treatments like statins and PCSK9 inhibitors and other interventions including obviously nutrition and exercise to try to reduce these cholesterol containing lipoproteins in our blood. But now begins a new era and I'm curious how people are going to react to it. My guess is that many people on the fence or skeptical in general will have visceral negative reactions. Keeping in the context that we just discussed in mind, we can now discuss Verve 102.

[00:05:32]This is a phase one early clinical trial in which participants with high blood cholesterol containing lipid proteins were exposed using a single exposure, a single dose of Verve 102. And here are the results. We're looking at the very same low density lipoprotein cholesterol that we discussed earlier. You'll notice the different doses of Verve 102 on the horizontal axis and the overall change in the LDL cholesterol on the vertical.

[00:05:57]Clearly, a 1 milligram per kilogram dose of Verve 102 leads to about a 60% reduction in LDL cholesterol. That's an incredibly impressive result. However, that result, while impressive, is not necessarily unique to Verve 102, as we've seen sizable reductions in LDL cholesterol using more traditional therapies that we've used over the last many years. The unique part is that people only had to take this therapy a single time and these measures are taken over two years. It's a little bit like taking a pill once and being cured of high LDL for two years. The difference here is that it isn't a pill, at least not yet. And the mechanism of action is infinitely more potent. Instead of using a molecule that blocks an enzyme or some other aspect of cholesterol production or elimination within the body, verve 102 is a gene therapy. So it acts on a particular gene within our liver cells called PCSK9. It's the very same PCSK9 that we have drugs that inhibit its function. Verve 102 uses a newer technology called crispercast 9 to replace one of its nucleotides that make up the PCSK9 gene sequence essentially introducing a mutation. This mutation then inactivates this gene stopping the PCSK9 from being produced. That's important because PCSK9 is involved in the removal of cholesterol containing lipoproteins from the bloodstream. So in short, active PCSK9 keeps cholesterol containing lipid proteins in the blood longer and inactivating it does the opposite. The overall point here being that a single infusion of Verve 102 leads to a gene change in the PCSK9 gene that leads to dramatic reductions in cholesterol containing lipoproteins.

[00:07:53]Now, we've covered a lot of the fascinating, but I think it's important to acknowledge some of the worries and I would even argue some of the downright scary. Before we get into that, I go over more information related to the Pisa study and the Mandelian Rand randomization trials. And I even get into the specifics of how Verve 2 102 reaches our cells, enters our cells, and ultimately affects our genes. I cover all that in the extended analysis of the one that you're currently watching. It's included as a physionic insider along with these perks right here and an accompanying article, a podcast, and much more. Plus, if you want to ask me more specific questions on the topic, you can also submit and ask questions in upcoming live sessions with me. To join the Physionic Insiders, just click the link in the description. Now, of course, since we're talking about gene therapy here, we also are talking about the scariest aspect of all this. The key advantage that things like statins and other cholesterol-lowering drugs have is that they're reversible. For the most part, you can just stop taking a treatment and reverse its effects. That is not the case with a gene therapy, at least typically. That means that the effectiveness of this gene therapy is going to depend on how many liver cells are affected by the therapy. In an ironic way, the more effective the gene therapy, the more your liver cells have been altered and mutated. So, while we only have two years worth of data, the assumption is that these lipoprotein particle reducing effects would remain for the rest of a person's life. We are essentially creating what we briefly went over with the Mandelian randomization trials. The issue may not be so much the reduction in cholesterol containing lipoproteins, but if there are offtarget effects of the gene therapy. In earlier versions of this gene therapy, there were some offtarget effects with increased liver harm, but supposedly these side effects have been addressed with this newer version. Even so, even in this initial clinical trial, over 70% of participants experienced some form of adverse event. To be clear, that doesn't necessarily mean serious side effects. That includes things like fatigue and mild reactions to the infusion. I would also note that it's also guaranteed that some people will experience some form of perceived side effect. Until we have comparisons against an actual placebo group, which we don't have here, it's impossible to know what is physiologically real and what isn't. So, apart from joining the X-Men, this is no doubt a serious commitment, maybe the most serious of your life. And while it could be proven otherwise in future research, it's certainly a scary prospect to consider mutating one's own genes for the rest of your life. I'll admit that for me, there is something attractive about having a path back when it comes to something like my own health. I would need to see extremely strong data and hear a compelling argument other than convenience for me to permanently shut down a gene within my body. But I'm sure that there are people that are far more adventurous with their physiology than I am. I'm quite curious on what your thoughts are. Anyway, this is fascinating, terrifying, and opens up many future gene therapies which will be equally terrifying. I would also quickly remind that heart disease and cardiovascular disease are not limited to plaque related heart issues. So this is this will not eliminate all heart disease. Assuming that it could get potent enough to reduce lipoprotein levels far enough, it could stop atheroscllerotic cardiovascular disease or at the very least slow it way down.

[00:11:38]We don't have that data yet. Like I said, let me know your thoughts. And if you haven't already joined the X-Men as a mutant or been scared off by the gene therapy, then I would highly recommend this next video. Thanks for delving into the world of gene therapy with me. What a wild world we live