Good morning, everyone, and thank you for joining us this morning at the 44th Annual Canaccord Genuity Growth Conference. My name is Whitney Ijem. I'm one of the biotech analysts here at Canaccord. And it is my pleasure to introduce Verve Therapeutics. And speaking on behalf of Verve will be co-founder and CEO, Dr. Sekar Kathiresan. Sekar? Okay, thank you very much, Whitney, and the Canaccord team for inviting us. So Verve Therapeutics is focused on cardiovascular disease, and our mission is to protect the world from its leading cause of death, and specifically a type of cardiovascular disease that's called atherosclerotic cardiovascular disease, or abbreviated ASCVD. This is the type where basically cholesterol builds up in the wall of the artery over time, leading to blockages and subsequent problems, like a heart attack. We have a good understanding of what causes this problem, and that's shown on the left. That's cholesterol carried in any of three lipoproteins: LDL, triglyceride-rich lipoproteins, or lipoprotein (a). And we actually have a good understanding of what can be a solution as well, and that's shown on the right. So basically, getting the LDL cholesterol low and keeping it low. So really important is not only how low you get it, that's the Y-axis on the right, but also how long you maintain that reduction. That's the X-axis. Both of them are really important. So how do we treat cholesterol right now? Well, there's a lot of pills and injectables that are available, some of them are shown here on this graph, that can bring the cholesterol down. Again, the Y-axis, 40%-60%. These medications are intended to be taken lifelong. The challenge really is that the treatment burden on patients to sustain a daily pill or intermittent injection over decades is very high. As a result, very few patients are actually on these medications for the required lifelong therapy. So up to 50% of patients discontinue the CVD medications just within 12 months. So for the majority of patients, despite the available therapies, they're basically not getting cholesterol lowering, certainly not for a lifelong treatment. So what we'd like to do is address this issue, address this unmet need of sustained, durable LDL lowering. And the way we hope to do that was a new treatment option, a one-time treatment that actually lowers LDL substantially and keeps it low lifelong, addressing both the how low, but also how long issue. And so this is the vision for Verve, these one-time treatment options, and we're advancing a pipeline of such medicines designed to lower cholesterol after a single treatment. And this is the pipeline. Let me walk you through it. The first column gives you the different targets. These targets all emerge from human genetics. These targets all have both pharmacologic validation as well as human genetic validation. Second column gives you the indications, and we've taken an approach where we're starting with a genetic form of high cholesterol first, and then moving on to broader populations. The third column gives you the different technologies we're using. We're using base editing as an approach to turn off a gene in the liver. For a couple of our products, we're also developing our own editors. There's also different delivery technologies that we've evaluated, and we've settled on a novel GalNAc lipid nanoparticle, which I'll tell you about in a minute. You can see after that, the different phases of development. Our program that's furthest along is VERVE-102. That's in the clinic right now. I'll tell you about that. The last column, importantly, is we have some very strong partners that are really excited about our mission and are looking to work alongside us to develop these medicines over time. And Eli Lilly and Vertex specifically are the two partners for our programs. And importantly, Eli Lilly we established a relationship last year, and they have minority rights for the lead two programs. Now, the pipeline itself can address ultimately a very broad set of individuals affected by cardiovascular disease. It's about 54 million people in U.S. or Europe. But this this overall large population can be broken up into distinct subsets that are shown at the bottom, where each of our programs address distinct subsets. These are largely non-overlapping subsets of individuals. And so you can see, for example, for the PCSK9 program, we're starting with a condition called HeFH, or abbreviation for heterozygous familial hypercholesterolemia. This is a genetic disease of sky-high cholesterol from birth. That's about three million people in U.S. and Europe. That's the group we're starting with for our lead program, and then we hope to expand broader from that. Now, let me focus on the lead target, PCSK9. We actually have two product candidates that we've developed or are developing for this target, VERVE-101, shown on the left, and VERVE-102, shown on the right. They're both for the same target, PCSK9 gene. They both use the same editing technology as something called adenine base editor that makes a single spelling change in the DNA of the liver to turn off a cholesterol-raising gene. They both use the same guide RNA to get the editor to the right place in the genome, and they differ largely in the delivery vehicle. So on the left, VERVE-101 has a certain set of constituents, lipid constituents, to make the lipid nanoparticle that carries the editor and the guide. On the right, VERVE-102 differs in those lipid components. And in addition, VERVE-102 has a targeting ligand to the liver called GalNAc that's added to the lipid nanoparticle. So the delivery system for VERVE-102 is the ionizable lipid, as well as the PEG lipid used in VERVE-102, has been well tolerated in more than 100 patients right now in third-party clinical trials. And because of the addition of the GalNAc, this lipid nanoparticle can get in through any of two receptors: the LDL receptor or the ASGPR receptor. Now, we have data for VERVE-101, and that's shown here. We've dosed 13 patients in the Heart-1 trial, and what we learned from that trial is that editing led to dose-dependent reductions in blood PCSK9 and LDL. It was a mean reduction of 46%, and there was durability after the one-time treatment, extending out to at least 9 months. Now, VERVE-101 had very good efficacy, but there were some safety challenges, specifically around transient laboratory abnormalities, liver function test elevation, as well as a platelet drop in a patient that led to us pausing the trial and ongoing investigation of the laboratory abnormalities to determine if we can develop some mitigation measures. So where we are right now is we understand from this initial experience with VERVE-101, that the editor and the guide work. The Heart-1 data showed us that we can edit in vivo in the liver for the PCSK9 gene to turn off the gene and lower cholesterol in HeFH patients. But we think that the safety issues, particularly the transient laboratory abnormalities, are due to the lipid nanoparticle delivery system, and that's what's been switched out, moving to 102 from 101. VERVE-102 uses a different LNP delivery system, as I described earlier, and so our current focus is on VERVE-102. We've gotten regulatory clearances in a couple of countries, and the Heart-2 trial, testing VERVE-102, is currently enrolling patients, and we're expecting interim phase I data for this product in the first half of 2025. Again, we think the editor and the guide are working well, and really iterating on the delivery system should solve the safety challenges we saw with VERVE-101. So this is the VERVE-102 product, which I described earlier. A brief description of the trial, again, focusing on patients with heterozygous FH, but also we've added another group of patients who require lifelong LDL lowering. These are patients who've had a heart attack at a young age, and these are premature coronary artery disease patients. So those two groups are being enrolled in this trial. Single-ascending dose design, several dose cohorts to find a safe and effective dose, and as I said, the trial is ongoing right now with data in the first half of 2025. Here are the milestones for the company this year and heading into next year, and really, the major one to focus on is the interim phase I data for VERVE-102 in the first half of 2025, allowing us to select a dose to take forward to phase II for VERVE-102, which we expect to start in the second half of 2025. Thank you. Excellent. Thank you for that. So I'm gonna dive in with a very high-level question, kind of going all the way to the end, which is pricing, which we sometimes get this question from people newer to the story. "Well, you know, millions of patients, and gene editing is expensive. Like, what-- how is this even gonna work?" So without obviously, it's early providing guidance, how are you guys thinking about pricing of, of a therapy like this in this patient population? Yeah, typically, when people hear gene editing or genetic gene therapy, they're thinking millions of dollars a dose. But that's certainly not gonna be us 'cause we, there's millions of patients, so there's a very large patient population. It's not a rare disease. And second is, I think we're gonna have a fair amount of flexibility because of the cost of goods, and typically, viral vector-delivered gene therapies, for example, are very expensive to manufacture. That's not the case for our product. It's basically mRNA package and lipid nanoparticle. Now, the COVID experience has taught us that this kind of product can be made very cost-effectively at scale. You know, the COVID vaccine, basically about 100 micrograms, costs about $3 to make. We're gonna be giving more like 50 milligrams intravenously, and even if you just scale up from that for amount, you're talking low thousands cost of goods. So the lots of patients and manageable cost of goods is gonna give us a fair amount of flexibility on pricing. Okay, that's really helpful. And then you kind of laid out nicely why editing is the right approach in this disease, for compliance and sort of long-term control reasons, and it makes a lot of sense as I look at the slide. Is that a case you have to make to patients and doctors as well, or is that pretty well understood, and I guess, do you have any market research that kind of indicates the level of demand or enthusiasm from, from both of those groups? Yeah, it's. We've done early market research, and there's actually remarkable receptivity to, by both providers and patients for this concept of a one-time therapy leading to durable health benefits. And part of that has to do with the fact that the cardiovascular community is quite used to one-time procedures for lifelong benefit. Think stent procedures, think bypass surgery, radiofrequency ablation for arrhythmias. Now there's even a new procedure for an ablation procedure for blood pressure called renal denervation. These are all one-time procedures that are permanent, that basically patients take up, physicians perform to be able to lead to lifelong benefit. In some sense, our medicine is really a molecular surgery. It's a one-time procedure to turn off a disease-causing gene. So there's actually a lot of openness to this concept. Fair enough. Fair enough. Okay, and then moving over to the transition from 101 to 102, which you talked about in terms of the novel LNP. You talked about some of the preclinical work that has shown, kind of confirmed that some of the safety issues were related to the LNP, and, and you've moved forward. I guess, how predictive are those preclinical studies, and how confident, I guess, are you that, that the issues are solved with the new LNP? Yeah, there's a couple of reasons that give us confidence. One is our preclinical work, and, second is the clinical, the lipids, the ionizable lipid and the PEG lipid used in 102, as I mentioned, has already human clinical validation. So let me talk through both of those points. So, on the preclinical side, when we, evaluate, 102 versus 101 in preclinical models, we see that 102, basically has a wider therapeutic index in terms of these issues, ALT and platelets, and so really confirming our hypothesis that it's the lipid nanoparticle. Now, we do often get asked: Well, how do you know it's a lipid nanoparticle? How do you know it's not the editor, for example, that's inside the cargo? The reason we know that is the experiments that we do in preclinical models actually have a scrambled guide, a guide that does not allow for editing. So that really isolates the issue to the lipid nanoparticle rather than the editing mechanism. In terms of the second piece of evidence that gives us confidence for 102 is the fact that the ionizable lipid and the PEG lipid used there has already been tested in third-party clinical trials, over 100 patients, and has been well-tolerated without LFT or platelet changes. So that, again, gives us confidence that this product, 102, will have the efficacy so that we saw with 101 but will not have the acute safety issues. Got it. Okay, perfect. And so on that point, as we look to the initial data from the Heart-2 study, what are you hoping to see, maybe relative to what you saw with 101? Is it, is it the same efficacy and just better safety? Is there room for more efficacy? How should we be thinking about that? Yeah, I think there's definitely a bar that we wanna cross, which is really a comparator out there that has the longest... You know, our key differentiating feature is durability, right? Lifelong effect. The product on the market that has the longest durability, Inclisiran, right now, which is an siRNA taken every few months, that product lowers LDL in heterozygous FH patients compared to baseline, by about 40%. And so I think that's kind of probably the bar we want to cross as a kind of a minimum bar, in terms of 40% LDL lowering. The key difference for us, of course, is gonna be lifelong benefit as opposed to a few months. So that's what we'd be looking for. Now, that 40% LDL lowering typically correlates with about a 60% blood PCSK9 lowering. So those are probably the two numbers to kind of keep in mind, as we think about the phase II data. Got it. Okay, The phase I data, sorry. phase I data. Yes, that's helpful. Okay, and then to the point on durability, understood kind of the focus is on Heart-2, to answer some of these questions, particularly on the new LNP. But from a durability perspective, updated data from Heart-1 could also be instructive. So I guess, can you remind us what was the amount of follow-up you had most recently, and is there a chance we could get an update on that from a durability perspective later this year, or is that also a 2021? Yeah, I think we announced a couple of months ago that we've seen durability out to 270 days in the earliest treated patient with a therapeutic dose. So that's a one-time treatment, and then about a 60% LDL lowering acutely, and then 9 months later, the LDL is still down 60%. So that's the human data, and follow-up is ongoing, and we'll likely be able to provide an update coming up on that. So with even further follow-up data. And so that's the human data. Now, in preclinical models, in non-human primates, we have durability out to 2+ years after the one-time treatment. So I think the durability issue here for in vivo liver editing is gonna be fundamentally different than viral vector gene therapy, where this is really likely to be a true one and done. Mm-hmm. Okay, fair enough. And mechanistically, you know, there's not, to your point, from a viral vector perspective, there are things that could happen that could maybe turn something off- Yeah ... or something, and that's just not, that's not happening. Exactly. This is editing the endogenous DNA, your own DNA, to make a single spelling change, and then when those cells divide, to give rise to new hepatocytes, they're basically carrying forward the edit that's been made, and that's why you have the durability. Mm-hmm. Okay, very helpful. And then looking towards the Heart-2 data next year, whenever we get that, what... Can you talk about how you're thinking about what you'll be telling us? Like, is there a certain number of patients, a certain amount of follow-up, and kind of the endpoints? Will it be very similar to Heart-1? How should we be thinking about it? Yeah, it's quite similar to Heart-1 in terms of the study design. So what we'd like to do, of course, the reason for the dose escalation is to identify an effective dose to take forward to phase II. So I think we'd like to put out a volume of data that gives people a sense of, you know, what that's gonna be, the phase II dose. So and then the follow-up, I think, you know, the last patient in will have minimum probably you know, 28, 30 days of follow-up. And but the earliest patients, of course, will have longer than that. You know, as I said, we've seen very good durability, so once you get to that nadir around day 28, then it's gonna be sustained over time. ... And then in terms of dosing of patients in Heart-2, is there still a stagger, and we should expect a patient enrolled dose and then wait some amount of time? Or, how should we think of the case? Yeah, it's very similar to 101. I think this is a standard for gene editing, gene therapy kind of field, where in a dose escalation, there's typically the first patient dose in a dose level. There's a bit of wait time between the first and second patient, and then there's a bit of wait time between each dose cohort, because a DSMB has to review the data from the first dose level, a certain amount of data, to be able to really allow for dose escalation to the next dose. So it is something that has kind of a built-in, you know, time mechanism. Yeah. Mm-hmm. Okay, fair enough. Understood in terms of wanting to have a relatively robust set of data before you communicate externally on Heart-2, but internally, I guess, how soon do you feel like you'll have the answer on the safety question with the new LNP? Is it, you know, within days after the infusion of some number of patients, you'll be able to tell? And so internally, you guys will have a better sense, obviously, as we externally await for formal data. Yeah, so the acute safety issues that we saw, which were transient laboratory abnormalities, so a rise in ALT or a drop in platelets in the one individual, those all resolved within a few days. So this is really something that we'll see if we're gonna see it within a few days after infusion. So that's what we'll be watching for. Okay. Of course, we wanna dose escalate to find the effective dose and then make sure that at that effective dose, we're not seeing the acute safety issues. Right. Okay, that's helpful. And then on the partnership side, as you've mentioned, you're working with Lilly. How frequently are you meeting with them? How frequently is information flowing back and forth? And then I guess you've also talked about providing them with an opt-in package, I believe, next year. So can you help us understand what that is? Yeah, so this gives me a chance to kind of describe our Lilly relationship. So, for the PCSK9 program, they have the ability to opt in at the end of phase I. And, if they decide to opt in, they're basically responsible for a third of worldwide development costs. In return, they get 50% of U.S. profits. The other 50% of U.S. is Verve, and 100% ex-U.S. is Verve. So this is really, I think, best characterized as, you know, we hold the majority rights, they hold minority rights, and that's for the PCSK9 program. Same relationship for ANGPTL3. And importantly, for both of these products, we retain control of development, and we book revenues. So again, this majority-minority kind of concept. We're super excited to have them on board, because, you know, they're excited about our vision, for kind of transforming the care of cardiovascular disease with this new approach. And they generally have taken this concept of, highly validated targets, and for each of those targets, multiple modalities. You know, pill, intermittent injections at various frequencies, varying frequencies, and then a one and done, and have all of those available in the marketplace. Mm-hmm. I think that's kind of the vision we're working toward as well, and we think a meaningful fraction of patients, when given a set of options like that, will choose the one and done. Mm-hmm. Mm-hmm. Fair enough. Okay, and then on the opt-in package, I guess, what is it? Yeah, sorry about that. So the package we deliver at the end of phase I is basically the data, the phase I data, and a development plan. So basically, and a budget for that development plan through registration. So then they get to look at that and say, "All right, I'd like to come in for that development. Mm-hmm. Okay, okay, got it. And I guess, like, is there anything we'll hear on the—that discussion, that dialogue, I guess, or is it? I think it's important to emphasize that, you know, we'll have our data. Mm-hmm. We'll deliver the opt-in package to them. So our data announcement is likely to come ahead of any formal decision from Lilly for opt-in. Got it. And then, you know, then there's a time period, because there's a built-in time period for them to evaluate the data and then, and then make a decision. Mm-hmm. But we highly suspect that they'll come in, based on the data. And then we'll be able to communicate that once they opt-in. Mm-hmm. Okay, perfect. And then moving over to VERVE-201 in the last minute or so, can you remind us, I guess, what's the status of that program? Is there anything you're waiting to see from 102 before moving forward, or is 201 just full steam ahead? Well, it's important to emphasize that that target, ANGPTL3, it's also cholesterol-lowering. It also adds triglyceride lowering, so it's kind of a twofer, and it's additive to LDL lowering based on the PCSK9 mechanism. So the opportunity here is very large. There's actually about 13% of patients with ASCVD on a statin and a PCSK9 still require additional LDL lowering, and that's the group called refractory hypercholesterolemia that we'd be able to look at here with ANGPTL3. There's also a rare genetic disease called homozygous FH we can look at for ANGPTL3 as well. So it's an important opportunity. It's LDL, you get the additional triglyceride benefit, and we are basically looking to, we're guiding to clinical trial initiation for that product in the second half of this year. And so it's using the same GalNAc-LNP that's being used in 102. And so the way we're looking at this whole situation is that, you know, with the 102 data coming up, really de-risks the delivery system, and that unlocks the rest of the pipeline. Because we're very confident in the cargo, the editing apparatus, we're gonna be de-risking the delivery system, and then the rest of the pipeline basically uses that delivery system. Mm-hmm. Okay, and a bigger picture question in the last 20 seconds, thinking very long term, is the idea to have, in your ideal world, a PCSK9 therapy and an ANGPTL3 therapy and an Lp(a) therapy, or is there some world where there could be one that kind of goes after all three, one therapeutic that does it all? The idea of multiplexing has definitely been of interest to us. It's something to really explore, 'cause the idea that because ANGPTL3 and LDL and PCSK9, they're additive mechanisms, putting them both together could give you very powerful LDL lowering. Mm-hmm. That's something we know we're exploring. Okay, and that's kind of relative to the, like, 40%-60% numbers you were throwing out. It's that combination that could drive things lower? Yeah, probably roughly closer to 70%-80%. Yeah. Gotcha. Interesting. All right. We'll stay tuned. Excellent. Well, thank you so much for the time. This has been very helpful. Thank you, Lynn.