Good morning, everybody, and welcome to Guggenheim's 6th Annual Biotechnology Conference. I'm Seamus Fernandez here for another fireside chat discussion with Verve Therapeutics. To my left is Sekar Kathiresan, Chief Executive Officer of Verve. Sek, thanks for joining us. Maybe we can just sort of start off and remind people what it is that Verve is seeking to do specifically in the area of your deep expertise, cardiovascular medicine and also genetic medicine. Well, thank you very much, Seamus. Delighted to be here. So Verve is developing gene editing medicines to treat atherosclerotic cardiovascular disease. All will have the same profile, which is a one-time procedure, a one-time treatment, permanent lowering of blood cholesterol. And the company is kind of born out of a deep conviction in basically one research insight, which is that if one's blood cholesterol is low, very low, lifelong, it's very hard to get a heart attack. And all of our products are really designed around that concept. Great. Super simple in terms of the message. But maybe you can talk a little bit about the complexity that's built into this, the complexity of actually doing gene editing, but also to some degree the complexity of actually advancing these medications into a patient population that has a lot of options. Yeah. I think we often get asked, "Look, there are other ways to lower cholesterol right now. Is there really an unmet need here?" There are statins. There's PCSK9 and siRNA medicines. There's PCSK9 monoclonal antibodies. So why do you need gene editing? And the best way to think about that is, yes, there are agents to lower cholesterol right now. They all lower LDL anywhere from 40%-60% in terms of after initiation of the medicine. But the challenge is, if you look a year out, after a patient is started on a cardiovascular medicine like a PCSK9 antibody, only about 50% are still on them. So the effective LDL lowering for these patients is not 40%, 50%, 60%, but like zero. And so there's still a huge unmet need. That's illustrated by the fact that only about 2% of patients eligible for a PCSK9 therapy are currently on them. Only about 50% of patients with atherosclerotic cardiovascular disease are on any LDL-lowering medication at all. Less than 5% of patients with heterozygous FH, the genetic form of high LDL, are at LDL goal. What we're looking to do, of course, is address that unmet need where you're able to, with a one-time procedure, lower the LDL deeply, but do it for decades. Great. And maybe in terms of the validation of your technology, can you just remind us where we are in the validation? Remind us the assets that we have, VERVE-101, prospectively VERVE-102 and VERVE-201. Maybe just remind us the targets and also where we are in kind of the validation approach with your technology. Yeah. So what we were able to accomplish in 2023 is showcase human proof of concept for in vivo base editing through our first program, VERVE-101, targeting PCSK9. We showed that the whole thing works. Basically, you can infuse a lipid nanoparticle into the bloodstream, one-time infusion. There's editing of the PCSK9 gene in the liver to turn it off. And the blood PCSK9 protein level comes down, and the blood LDL comes down. So I'll walk you through those results in a couple of minutes. Taking one step back, though, kind of how we're set up, the targets we've chosen, three major targets, PCSK9, ANGPTL3, and LPA, reflect the three major axes of lipid risk, lipoprotein risk for heart disease. That's LDL, triglyceride-rich lipoproteins, and lipoprotein(a). Each of the three targets addresses each one of those lipoproteins. And we chose these targets for gene editing because the number one issue is, is it safe to permanently turn off these genes in the liver to lower LDL or triglycerides or lipoprotein(a) lifelong? And for these targets, there are humans. Each of these targets, there are humans walking around who completely lack the gene. They basically have it turned off naturally, human knockouts. And they're healthy, and they have lifelong low LDL or low cholesterol. So the human genetics shows us that it's safe to permanently turn off these genes in the liver. The second criteria for each of these targets is that there are prior treatment modalities that have been developed against these targets and have been given to patients. And those medicines have been shown to be effective and safe. And that's the case for each of the three targets. So that's how we chose the targets. Then the editing technology, we've been flexible as to how to edit to turn off these genes in the liver, whether it's by genetic scissors, the so-called standard Cas9, or base editing, which is more like a pencil and eraser. We got access to each of these technologies and have directly compared these technologies in cells, mice, and non-human primates and made a choice based on those data. So for our first couple of programs, we've chosen base editing as a technology. So that brings us, I think, to VERVE-101, the clinical trial. Great. And maybe you can just describe the clinical trial data, Late- Breaker at AHA last year. And from a validation of the technology perspective, I think the result was certainly very powerful. In terms of the patient population, I think there's still some residual confusion as to the population of patients that you were sort of forced to study. And so can you help us understand a little bit of the patient population that, with the gene editing technology, you initially had to go into? And what impacts that you believe that had on some of the perception of safety of the product? Yeah. So the Heart-1 trial tested VERVE-101 targeting PCSK9. This is a base editing medicine, basically an mRNA for the base editor, a guide RNA targeting PCSK9. Both those nucleic acids are packaged in lipid nanoparticle, delivered as a one-time intravenous infusion. This is a single ascending dose design study, roughly three patients in each of four dose levels. The patient population was individuals with heterozygous FH, but really the sickest of the sick. The reason it started there is it's a brand new treatment modality. The FDA guidance on human genome editing that came out a couple of years ago was pretty clear that the initial patient population should be that with severe advanced disease. But they also highlighted in that guidance that patients with severe advanced disease, though that's the place they want us to start, are more likely to experience AEs and, as such, make safety maybe more difficult to interpret. And then they said, "So therefore, in some cases, it may be okay to move on to patients with less advanced, more moderate disease." And you'll see that's the transition we're making. But the patients we enrolled were patients with severe advanced HeFH, heterozygous FH. They already suffered a heart attack, many of them multiple heart attacks or bypass surgeries. And they had a very high LDL on maximally tolerated oral standard of care. Just to give you a sense of that severity, their LDL on therapy was 193 mg/dL. Most of the previous studies in this space with the other agents were starting LDLs closer to low hundreds. So anyway, that's the patient population. That's where we started. What we saw in the trial was the first couple of dose levels, a minimal effect. But we treated 3 patients at potentially therapeutic doses, 0.45 mg/kg and 0.6 mg/kg. We saw dose-dependent reductions in both PCSK9 and LDL. And importantly, the LDL reductions were ranging from 40%-55%, well within the range that we expected going in based on the prior treatments and based on what this mechanism can accomplish in these patients. So really very nice human proof of concept for the technology. This is the first time that base editing has been shown to work in humans for in vivo. On the safety, there were three observations. One is infusion reactions. This is expected based on lipid nanoparticle treatment. This is body ache, fever, headache, self-resolves with treatment, Tylenol. That was not bothersome. Second is there's a transient rise in liver function tests in some patients with lipid nanoparticle infusion. We saw that. That, again, reversible, no injury, something very manageable for a one-time therapy. Then in these severe advanced ASCVD patients, there were two CV events. One clearly unrelated. The second labeled as potentially related based on the timing with respect to dosing. Overall, these events have been reviewed by the DSMB, an independent academic DSMB, reviewed by the FDA as well. The DSMB basically said, "Look, this is consistent with severe ASCVD. You should continue dosing without any modification." The FDA looked at it and gave us the IND clearance to dose patients in the U.S. And then the third group that's looked at it, of course, is Eli Lilly. And they ended up purchasing the product rights for these two products from Beam, the minority product rights, after seeing all these data as well. So we feel very comfortable with where we are. And the changes we're making, you kind of were going forward. So we're continuing to enroll at 0.45 and 0.6. We'll complete the SAD phase this year. We're guiding to additional data in the second half of this year. And we're making that transition that the FDA kind of mentioned, which is moving from severe advanced disease patients to less advanced, more moderate disease ASCVD patients. And we're doing that in a couple of ways, which we can talk about. Great. Yeah. So in terms of those modifications, this is not a modification that FDA would bring on. It's a modification that you're able to make to enroll patients who are less likely to have maybe inherent AEs that clearly would not necessarily be related to the product, but unfortunately related to their existing underlying disease. Are there ways to actually manage that specifically and are you doing anything? Yeah. I think the most important thing is to manage that in the context of an open label phase I, right? When we get to phase II, we'll have a control group, a placebo group, where you'll have a background rate of events that you can compare in treated versus untreated. In this case, for phase I, we don't have that luxury. And so you do want to try to reduce the background event so that there's not this confusion about is a drug related or not. And the way we're doing that going forward, now that we have experience in the first 10 patients, is two ways. One is there's some protocol changes to allow for more moderate disease patients. Second is, in every patient coming in, prior to enrollment, we are doing a CT scan test called a coronary CT angiogram. It's a non-invasive dye test that can tell you if there are blockages in the heart arteries. We are using that to exclude patients with obstructive disease. That should bring down the background event rate now. Great. And then just in terms of new datasets or follow-up data that could be presented, whether it be from that first cohort or the incremental cohort being recruited under the U.S. IND, when might we see some additional data? For VERVE-101 targeting PCSK9, we're guiding to additional data for the Heart-1 trial in the second half of this year. That'll be taking the trial where it is now to completion of the SAD phase, which will be about 15 or 16 patients total. We also will have durability probably extending to more like 12-15 months from the 6 months longest that we had when we presented at AHA. So those are really probably the two key items for this year for 101. For VERVE-102, which we can get to in a minute maybe, we'll be initiating the clinical trial in the first half of this year. Then the third major milestone for the company is for the ANGPTL3 product, VERVE-201, we'll be starting the clinical trial in the second half of this year. So by the end of this year, we'll have patients enrolled for all three programs. Clinical data will be in the clinic for all three programs. Great. 102, maybe we can talk a little bit about the differences between 102 and 101 just as a sort of preliminary starting point. Then we can maybe talk a little bit about Lilly's involvement. Yeah. So for 102, it's the same editor, same guide. So it's the same active ingredients. So those have already been de-risked based on 101's data. The delivery vehicle is different. So in two ways. One is the ionizable lipid component is different. And then second is we've added a targeting ligand called GalNAc to the LNP so that this LNP can get into the liver through any of two receptors, the GalNAc receptor, which is ASGPR, or the LDL receptor. So this delivery vehicle gives potential advantages in terms of maybe you get the same level of efficacy that we're nicely seeing with 101, but you could get it at maybe a lower dose. And so our explicit strategy over the last couple of years has been we have two products that look really good, each look really good in non-human primates. The whole field of in vivo liver gene editing, the major unknown has been the monkey-to-human translation for any given lipid nanoparticle. And there haven't been that many examples to date of what that looks like, just now, just Intellia and us. And so we want to ultimately make a decision on what product to take forward to later stages of development based not just on preclinical data, but directly looking at the two products and patients. And so we're going to. going to. That's what we're doing. So basically a bake-off in phase I. Got it. Just in terms of the maybe editing efficiency, is there an opportunity for just more efficiency, not just with ability to go after lower doses, but perhaps to see more consistent LDL lowering over time? That's right. I think the consistency of the editing could be one of the differentiating factors. At any given dose, how consistent does that affect? Is every patient getting saturation editing at that dose? And certainly, you could see differences there between 101 and 102. And that's the kind of thing we'll be looking for to make a decision once we have that human data. Great. And just in terms of the sort of time point for that decision, is that a yeah, maybe you can just give us a sense of? Yeah. That's a 2025 story. I think the goal would be in 2024 to get 101 done, start 102, make good progress there, finish up 102 in 2025. Then 2025 will be all about the clinical data comparing 101 and 102, making a selection, and starting phase II. That's around the time we expect Lilly to basically opt in and start chipping in for the development expenses. That kicks in for them essentially at phase II. Great. And can you just remind us the importance of having a collaboration partner once you sort of enter phase II? And also what sort of Lilly's responsibilities would be should they choose to opt in? Yeah. So 2023 was a big year for Verve. We got human proof of concept for this new treatment modality. We got the FDA on board. We did a fundraise to give us a 3-year runway to the late 2026. And then one of the most important developments actually is gaining Eli Lilly as a partner. Lilly came on board by purchasing the product rights that have been previously held by Beam. These are minority product rights. And what Lilly purchased from Beam for about $600 million total deal value is the right to 50% of US profits. And to get that, they have to pay a third of worldwide development expenses from phase II onward and 50% of US commercialization expenses. Importantly, Verve retains the other 50% of US profits and 100% of ex-US. And Verve controls development and books revenues. But we were super excited to get Lilly on board because of their considerable experience in the cardiometabolic space, and particularly in late-stage development for a lot of these indications. And they have deep conviction. They share our conviction, I should say, in taking this technology to large indications. And so having them on board is going to be helpful in many, many ways as we take these products forward. Great. Maybe just remind us some of the complexity of treating HeFH versus HoFH and why ANGPTL3 is important as an incremental target. Yeah. That's great. So for HeFH, which is about 3 million people in U.S. and Europe, PCSK9 is a great target. And that's where we started. And the expansion from HeFH for PCSK9 will be garden variety atherosclerotic cardiovascular disease. And that's about 54 million people in U.S. and Europe. So the addressable market for the PCSK9 program is just huge. For HoFH, which is a second type of genetic form of high LDL, this is a rare orphan disease, homozygous FH, rare orphan disease, 3,000 people in U.S. and Europe, LDLs of like 500, 600, 700, heart attack at very young ages, bypass surgeries at young ages. These patients completely lack the LDL receptor. Both copies are broken. In these patients, the PCSK9 mechanism actually doesn't work because the PCSK9 mechanism requires some amount of LDL receptor. In addition, in these patients, standard lipid nanoparticle doesn't get taken up because uptake of LNPs into the liver is actually a little bit dependent on the LDL receptor. So we've developed a program targeting ANGPTL3, which is an LDL lowering target that will lower LDL in homozygous FH patients. And we put that target, that construct, to be the GalNAc lipid nanoparticle because that GalNAc lipid nanoparticle can get into the liver using a mechanism other than LDL receptor, that ASGPR receptor, which is the GalNAc ligand. So the ANGPTL3 product, VERVE-201, is perfectly designed for this homozygous FH patient population. That's what we're going to start. And the registration path, the precedent, is actually quite a bit different. This is a standard rare disease path where, for example, the monoclonal antibody targeting ANGPTL3, Evkeeza, by Regeneron was approved based on a registration study of about 60 patients. And that product is a once-a-month IV infusion. And so we are going to be developing ANGPTL3 in HoFH first. But even this product, ANGPTL3, VERVE-201, has the potential to expand to a broader patient population called refractory hypercholesterolemia. These are patients who have uncontrolled LDL on statin plus PCSK9. So each of our programs is designed in the same way, which is start with a genetic subset and then expand out. You see that for PCSK9, and you're going to see that for ANGPTL3 as well. Now, the ANGPTL3 program is right now we're guiding to starting in patients in the second half of this year. Perfect. It doesn't stop there. There's LPA. But you also have another program that you sort of successfully partnered with Vertex. So I know you can't talk about the Vertex program, but maybe you can just talk about the partnership and what Verve has actually been able to do being sort of technology agnostic. Yeah. So our strategy, as I said, we pick targets of high conviction. We're open to a range of different editing tools. And you've seen that in our pipeline. For the Vertex collaboration, what got us excited about working with them and they approached us because of our progress on delivery, GalNAc LNP, and the efficiency which we were seeing in non-human primates. And they wanted us to work on this liver disease of interest to them. This is our first program that's non-cardiovascular. And we're excited to work with them because they're Vertex. They're an amazing team. Learn a lot from them. They clearly have gotten the first CRISPR approval. So there's a lot to learn for us. Second, this allows us to basically develop some new editing capabilities, new editing tools. And they're paying for all the research costs through phase I. So it was a great setup. What we've done is made progress against that target, developing a new editing approach. It's still not disclosed in a research phase, but there's been very good progress. And then last question, LPA. I know we have short time, but what are you watching in terms of progress with LPA? And how important of a target do you think it's likely to be? Well, so we started the company in 2018 with three targets, PCSK9, ANGPTL3, LPA, because of that conviction that these are the three major axes, independent axes of risk. Why LPA is important is people with very high LPA, it's non-overlapping with people with very high LDL. They're different people. And it's an independent risk factor. And previously, there's no ways to treat it. It's entirely genetic. You can't do anything about it. You can't eat your way or you can't eat less or lifestyle-wise change it. You're born with your LPA level entirely determined by inheritance. So it's a good setup for a one-and-done therapy. People who have very high LPA, they have a heart attack, premature heart attack. I think a one-time treatment that gets rid of it permanently will be a good thing. What we're watching for is there's other therapies that are in development, ASO and siRNA. And there's outcomes trials ongoing right now. And I think the result of those outcomes trials will be very helpful to understand the dose response. How much LPA lowering do you need for a given degree of event reduction? We know that exquisitely well for LDL, but these two trials, Horizon and Ocean, will be the first two for LPA to establish that relationship. So that'll give us a good sense of what we need to accomplish. This program is partnered with Lilly. Again, Lilly has an siRNA against LPA. They have an oral program, small molecule against LPA. They were looking for a gene editing solution. They came to us, and we're really excited to work with them on this as well. Great. Well, lots going on. I'm sure a lot of interest. Thank you, Sekar and Verve, for joining us here at our conference. Look forward to all the data that's to come in the next 12-18 months. Thank you so much, Seamus.