Is Lifelong LDL-C Lowering Within Reach? The heart-1 Gene-Editing Trial

This transcript has been edited for clarity.

Michelle L. O'Donoghue, MD, MPH: Hi. This is Dr Michelle O'Donoghue, reporting for Medscape. I'm here at the American Heart Association meeting, and one of the interesting stories that we're going to be talking about is that of gene editing.

Joining me to discuss this is Dr Sekar Kathiresan. He's the co-founder and the chief executive officer of Verve, and they presented some very interesting results. Before we get into the results, let's take a step back and talk about the field in general. There are many people who may not be familiar with gene editing, so maybe you can walk us through a little bit of the basics.

CRISPR Scissors vs Eraser

Sekar Kathiresan, MD: Michelle, thank you so much for having me. As you know, the gene-editing technology was initially described in 2012 by Emmanuelle Charpentier and Jennifer Doudna, and the first generation of this technology, or so-called genetic scissors — that's really the analogy — is CRISPR-Cas9.

How CRISPR-Cas9 works is, when given a guide RNA, it goes to a specific place in the genome based on that address that you gave in the guide and then directs a cut. It basically cuts the DNA entirely at that intended spot and has been used to basically turn off genes. That's really the major way that it's been used. The first of the medicines using that technology, called exa-cel, being developed for sickle cell disease, is the furthest along and likely will get FDA approval by December. That's the first-generation technology.

The second-generation technology is called base editing. Base editing differs from standard CRISPR-Cas9 in that the base editor doesn't cut DNA but chemically converts one letter to another. It's more like a pencil and eraser, where it can go to a specific spot in the genome, erase a letter — let's say an A — and change it to a G. That can be used to fix mutations, or in our case, we're using it to turn off a gene.

O'Donoghue: There's a large amount of potential here, certainly, and I know that PCSK9 is a target of particular interest for you. That's where you're starting. Would you walk people through what you have right now, what you presented today?

Kathiresan: What we presented today are results from the heart-1 trial, with VERVE-101. This is a first-in-human study of this new technology. Why are we doing this? There are other medicines available right now to lower cholesterol, such as siRNA and monoclonal antibodies. The major issue we see is that, despite the availability of all these medications to lower cholesterol, the fraction of patients who are actually on an LDL-lowering medicine, who've already suffered a heart attack, is actually very low.

We think much of that has to do with the chronic care model, the idea that somebody has to take a daily pill or intermittent injections for decades for LDL care. What we'd like to do is replace that chronic care model or really disrupt that model with one-and-done treatments. Imagine a future where you get a one-time intravenous infusion and a lifelong LDL-C lowering. That's the idea behind Verve.

heart-1 Study and Long-Term Safety

O'Donoghue: We know that noncompliance is an important issue. Many of our patients, where we're sending them out the door with prescriptions for statins, for instance, a large amount of those prescriptions go unfilled. Even with the PCSK9 inhibitors, we now have some therapies that last longer, but certainly not the one-and-done approach that you're talking about.

Now that we're seeing patients who seem to be having more and more early onset of premature coronary disease, the idea facing a 40-year-old who needs to take a lifetime of regular treatments, it's very daunting for them. I think that there is certainly appeal in the idea of approaching this through gene editing.

What do you say, though, on the flip side about people who express concerns about this type of an approach? I mean, one-and-done is great on efficacy, but of course there are going to be the concerns about the safety ultimately.

Kathiresan: There are several aspects of safety, right? One is the gene itself. What gene are we turning off and why do we think it's safe to turn off the PCSK9 gene permanently? That actually comes from human genetics. There are people walking around who have this gene naturally switched off lifelong. They have very low LDL, they're remarkably protected against heart attack, and they're otherwise healthy.

This is what gave us the inspiration that there are some genes in our body that are truly spare parts. You can get rid of them and all you get is health. PCSK9, believe it or not, seems to be one of those. Our goal is to basically switch off the PCSK9 gene in the liver to mimic that natural situation where people are protected.

We started with this idea in 2018. In 2020, we got it to work in nonhuman primates, monkeys. Last year, we dosed our first patient. This year, we've announced the results from the first 10 people in the phase 1 trial.

The drug itself is an mRNA for the editor and a guide RNA. Both of those are packaged in a lipid nanoparticle. That lipid nanoparticle is infused into the bloodstream. It's a one-time intravenous infusion and it's very simple. It's a peripheral IV.

After the infusion, the drug makes its way to the liver. It's taken up almost exclusively by liver cells. Once inside the liver cell, ultimately, the editor goes to the right place in the genome and makes the A-to-G spelling change at one spot in the PCSK9 gene to switch it off. Switching off the gene reduces protein production. The blood levels of PCSK9 and the LDL-C should go down. That's the theory.

We've treated 10 patients so far. Now, what type of patients should we treat with this new therapy, a brand-new modality and first of its kind? The FDA guided, last year, on the appropriate patients for a phase 1 clinical trial that incorporates human genome–editing products. They said that you should study people with severe, advanced disease.

As you know, most phase 1 studies are healthy volunteers, but the patients we've enrolled are by no means healthy volunteers. They're the sickest of the sick. The patients we enrolled have heterozygous familial hypercholesterolemia, they already have established atherosclerotic cardiovascular disease (ASCVD), often multiple procedures, and multiple myocardial infarctions. The mean LDL-C was 193 mg/dL on maximally tolerated oral therapy. We had these patients and we enrolled them.

There have been four dose levels that have been administered, with three patients at each of the first three dose levels, and one patient at the fourth dose level. With the first two dose levels, there was minimal response on either the PCSK9 or the LDL-C after infusion. With the third and fourth dose levels, the potentially therapeutic doses, we've treated three patients. We found that the PCSK9 reductions were in the range of 47%-84% reduction. The 84% reduction is pretty sizable because about 85%-90% of the blood PCSK9 protein comes from the liver. The fact that in that one person we've got an 84% reduction means we probably edited nearly every hepatocyte. Both copies of the gene turned it off.

In terms of LDL-C, the real clinical endpoint, we again didn't see much of an effect at the first two dose levels. At the two highest doses, we've seen LDL-C reductions of 39%, 48%, and 55%, which is a range that is well within what the current medications available offer and within what our therapeutic product profile was.

Let me move to durability. We have durability data out to 6 months right now in the longest-treated patient with efficacious dose. The LDL-C came down 55% at 28 days, and then 6 months later, the LDL-C is still down 55%. This is very reminiscent of the nonhuman primate data, the monkey data, where we gave a one-time treatment and then 2.5 years later, the LDL-C is still down 60%. This really gives us some confidence that with longer follow-up, we'll have the durability that we're looking for. That follow-up is ongoing.

O'Donoghue: It's in line with what we'd expect to see with the PCSK9 inhibitors that are currently available. Here, the durability piece is what's really intriguing and exciting. What did you learn on the safety side, appreciating that there are small numbers?

Kathiresan: There are small numbers and it's a phase 1 in patients with severe ASCVD. We saw three things. The first two are lipid nanoparticle infusion related. In patients at the 0.45 mg/kg and 0.6 mg/kg, the two highest dose levels, patients experienced flu-like symptoms during infusion, and shortly thereafter that resolved pretty much on its own, or sometimes with just Tylenol. These symptoms are fever, body aches, and headache. This is something that's expected.

The second is that there's a transient rise that's reversible in liver function tests, specifically alanine transaminase (ALT), with the infusion in the two highest dose levels. The peak ALT is four or five times normal, but then it comes back down, and within a week or so it's back to normal, with no evidence of liver injury. Again, that was anticipated based on the preclinical data in nonhuman primates.

Of the 10 patients, two have had cardiovascular events, really due to their underlying severe ASCVD. One patient suffered a fatal cardiac arrest 5 weeks after infusion. That patient had a history of prior cardiac arrest and ischemic cardiomyopathy at baseline. An autopsy was done and showed severe underlying coronary disease and no evidence for myocardial inflammation, myocardial infarction, or a pulmonary embolism. The data safely monitoring board (DSMB) determined that this event was unrelated to treatment.

The second participant suffered a myocardial infarction, and that was determined to be possibly or potentially related to the treatment because of the proximity to the dosing. However, this patient had unstable angina coming into dosing — chest pain with exertion that he did not disclose to the investigators. After the treatment, he went to angiography and the angiography showed multivessel coronary disease, incident restenosis involving all the major arteries, as well as an obstructive lesion in the left main artery. These were all preexisting.

I think it was unfortunate that the patient had not revealed the symptoms that he had, but as you know, these things happen sometimes in early clinical studies. Again, the DSMB felt that this was due to the severe underlying disease and encouraged us to continue dosing.

These data have also been reviewed by the FDA when we submitted our investigational new drug (IND) clearance request, and they've cleared the IND. We are now ready to initiate this study in the United States. Currently, the study is ongoing in the UK and New Zealand, and now with the US clearance, we'll be able to start enrolling patients in the US.

O'Donoghue: As you say, these are sick patients and they're small numbers. Ultimately, we will need to see the safety profile in a larger group. In terms of the efficacy, I think it's very interesting to see these early results. The durability will be terrific to watch as time goes on.

Key Takeaways and What's Next

Kathiresan: There are two major takeaways from this work. On the scientific side, this is really the first time that it's been shown that you can change a single letter in a single organ in a human being for a clinical effect, so-called in vivo base editing in humans. On the clinical side, it's early, but this could open the door to an entire new way to treat heart disease: rather than daily pills and intermediate injections, a one-time intravenous infusion procedure and then lifelong LDL lowering.

O'Donoghue: To that point, what else do you have in your pipeline? As you say, it opens the door to many different possibilities.

Kathiresan: We've been very focused on the different axes of lipoprotein risk for heart disease. As you know, cholesterol in the blood is carried in any of three different particles: LDL, triglyceride-rich lipoproteins, and a particle you know very well, which is lipoprotein (a).

The PCSK9 program addresses LDL. We have another program that targets the ANGPTL3 gene. It turns it off in the liver, and that targets LDL and triglyceride-rich lipoproteins. Then we have another program that targets lipoprotein (a). We envision a future where the appropriate patient may get either one or a combination of these treatments to get lifelong lowering of blood cholesterol and avoid heart attack.

O'Donoghue: We'll stay tuned because I think that there are many interesting developments that will be seen on this front in the years to come. Thanks again for joining me today.

Kathiresan: Thank you so much, Michelle.

O'Donoghue: Signing off for Medscape, this is Dr Michelle O'Donoghue.

Michelle O'Donoghue is a cardiologist at Brigham and Women's Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she's never strapped on hockey skates.

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