Thanks, everyone, for joining us, and welcome to the Goldman Sachs 45th annual healthcare conference, first day. Super excited to have, Verve Therapeutics, Sekar Kathiresan, CEO, join us here today. Thank you, Sekar. A real pleasure to be here, Andy. Thank you. Yeah, of course. So maybe we could start with an overview of your approach in cardiovascular disease, and to help level set for us why you believe that a one-time gene-edited therapy is the right approach here. So Verve Therapeutics is developing one-time gene-editing medicines to treat cardiovascular disease. Think one-time treatment, permanent lowering of blood cholesterol. And I would say there are like five reasons as to the why, okay? Number one is that this is the answer to heart attack. It's pretty clear that if one's LDL cholesterol is really low, lifelong, so let's say like 50 milligrams deciliter, lifelong, it's very hard to get a heart attack. That's probably the main reason to really pursue this strategy. Number two, there's a huge unmet need. As you mentioned, there are a lot of treatment options right now, but time on treatment is really low. Despite the fact that there are several pills, multiple injections, less than 2% of patients with familial hypercholesterolemia are actually at LDL goal. And we can talk about maybe why that's the case. The third is patients actually prefer a one-time functional cure compared to having to take injections for their whole life. The fourth reason is there's a large market opportunity. And just to illustrate that, the PCSK9 medications to lower cholesterol, there are three injections right now available. As a class, that class is expected to sell about $3.6 billion annualized based on first-quarter sales. Now, that $3.6 billion, believe it or not, represents just 2% of eligible patients. So there's a huge market opportunity. And then lastly, I think, I want to address a pretty common misconception about our therapy regarding commercial. I think most people think when they think one-time medicines, gene-editing medicines, they're thinking millions of dollars a dose. That's clearly not going to be us because we ultimately want to treat millions of patients. And we're going to have the flexibility to do so because we have lots of patients. That's not a rare disease. And second, the cost of goods here could be quite manageable because our drug looks like the COVID vaccine in terms of mRNA packaged in a lipid nanoparticle. And we know that kind of product can be made very cost-effectively at scale. Maybe a follow-up there, since you've touched on the commercial opportunity. I guess maybe what is your understanding of the interest from patients to embark on this new type of therapy? It's very different from your orals, from even your PCSK9, RNAi therapies that they may be more familiar with. What is the appetite there? The appetite is quite high. And I'll give you a couple of analogies in one kind of survey data. I think, you know, I practice cardiology, preventive cardiology for 20 years at Massachusetts General Hospital. And patients are quite used to one-time therapies in cardiovascular medicine that are permanent, irreversible, intended for lifelong benefit. So think bypass surgery, think stent procedures, think renal denervation for blood pressure, or, you know, radiofrequency ablation procedures for atrial fibrillation. So these are all other one-time procedures. And so I think our medicine is ultimately going to be less a drug, I would say, and more a one-time molecular surgical procedure. So that's really the analogy I think we've been trying to talk about. And it's very comfortable for patients and for physicians as well. In terms of the appetite, I think quantitating that, you know, there's a survey done of a couple thousand patients recently who had high cholesterol or already had a heart attack, required lifelong LDL lowering. And they were given four options: a daily pill, twice-a-month injection, twice-a-year injection, or a one-time gene-editing therapy. And, the proportion of patients who chose each one of these was a third for one-time gene-editing therapy, okay, about 40% for pills, 4% for twice-a-month injection, and 14% for twice-a-year injection. So already at this stage, a third of patients would be open to a one-time functional cure. And this is, you know, I think, a very good indication of the potential appetite. Do you find that your colleagues, cardiologists, other physicians are as readily excited about this move away from a chronic therapy? Absolutely. Because they're very frustrated by that low time on treatment. You know, theoretically, the current medications can lower LDL anywhere from 40%-60%. These are the pills or injections. But about 50% of patients, one year after starting any cardiovascular medication, are no longer on them. Think about that. 50% of patients are no longer on them. So their effective LDL lowering is not 40%, 50%, 60%, but zero. And that frustrates physicians. And so the idea that you could have a one-time therapy that lowers LDL for the rest of that patient's life would is really a pretty dramatic option. Got it. Well, let's jump into your first clinical data you had last November. As a cardiologist, maybe help us contextualize how meaningful that was, to see the first gene-edited therapy here. Yeah. So when we started in 2018 with this concept of one and done for the largest disease affecting the world, people thought, frankly, we were a little bit nuts, in terms of whether it would even work, and because there had been no prior examples of in vivo base editing, in anything larger than, you know, cellular models. So over the six years of the company, from 2018 to 2024, we've basically gotten the product concept to be effective in cells and mice, non-human primates, and then this past year we showed in humans that you can base edit. And what I mean by that is make a single base pair change in one spot in the PCSK9 gene to turn it off permanently. We can base edit pretty much every liver cell. As a result, the blood PCSK9 protein made by that gene comes down dramatically, and then the cholesterol comes down dramatically. We've treated about 13 patients overall, seven of them at potentially therapeutic doses. We saw a range of LDL lowering from about 25%-70%. In that 70% patient provides that really strong proof of concept that it is going to be possible to edit nearly every liver cell in a human being to turn the gene off and have dramatic LDL lowering. Importantly, the durability of this effect, we already are now seeing out to 9+ months after the single treatment. This really is reminiscent of our monkey data, where we have data now almost out to three years after the one-time treatment in the non-human primates. So this is very strong proof of concept that the, the base editing approach is going to work. Now, at potentially therapeutic doses for this first product, VERVE-101, we picked up some safety signals, specifically transient laboratory abnormalities, so a rise in liver function tests, a drop in platelets in one patient, that really, made us, pause this study and really try to understand, can we develop mitigation measures to avoid these transient lab abnormalities? And then meanwhile, we are going forward with a second-generation product, that uses the same editor and the guide, that to get the editing to happen, but has a different lipid nanoparticle formulation. So this is called VERVE-102. That trial just started. And we believe this product will solve the laboratory abnormalities we saw with VERVE-101. And we can talk more about that. Got it. Maybe quickly on the 70% LDL lowering, maybe help put that into context for us relative to other therapies that are out there. What is the bar for new therapies as they come onto the market or as they're being developed, to really have a meaningful impact here? Yeah. The bar is really about, not only how low you go, which is often what people focus on, the percent reduction, but how long. So because the name of the game here for cholesterol lowering is not only how low, but how long. So our differentiating feature, of course, is the duration of therapy, right? Because you want the cholesterol, it's all about the kind of area under the curve. So, the existing therapies on the how low are anywhere from 40%-60%, based on the kind of patient population and the specific modality, okay? But the existing therapies, as I mentioned to you, for the average person, time on treatment is a few months, maybe six months, maybe a year. But the majority of patients are off the medicines at a year. So we're going to want to match, I think, the existing therapies on how low, but how long, that's going to be, you know, our key differentiator. So that how low, I think, is 40%. So just using inclisiran as an example, which is the siRNA from Novartis and, previously developed by The Medicines Company, that medicine in HeFH patients, which is one patient population, the first patient population we're going after, this is a genetic form of high cholesterol from birth. In those patients, compared to baseline, in inclisiran, lowers LDL by 40%. In patients, the garden variety patient, it lowers LDL compared to baseline by 50%. And so those are, I think, reasonable benchmarks for us in terms of the how low. But how long, again, is going to be the key differentiator for us. Got it. So then with the work that you're doing right now to understand the signal that you observed in VERVE- 101, where does that stand? And when can we expect an update? Yeah. I think that work is ongoing. It's nonclinical studies to understand the mechanism by which some of these laboratory abnormalities occur. But most importantly, it's really, can we figure out a mitigation measure? Because if we can, then there very well may be a path forward for 101, where we love the safety signal, I mean, the efficacy signals we saw. We just want to, really avert those safety signals. What underpins your belief that it is the lipid nanoparticle versus the editor versus the guide? It's a great question. It really is very compelling preclinical data that if you take the lipid nanoparticle and put inside cargo that is not capable of editing, so it's basically mRNA plus inactive guide, and you give that construct to animals, you get the same laboratory abnormalities. Really pointing the finger at the delivery system and rather than the cargo. The delivery system is what's been switched out for between 102 and 101. Got it. Maybe if you don't mind, digging more there, what really does differentiate the different delivery systems? You have a different ionizable lipid, as you've mentioned. Maybe help us understand. Yeah. I think this is another large misconception in the field. You know, when people say, "Oh, use a lipid nanoparticle," there's no such thing as a single lipid nanoparticle. It's like, you know, it's really different chemical matter that's put together to get to that spherical shell. The lipid nanoparticle typically has four components, and each of those can be different across nanoparticles. So the four components are an ionizable lipid, a PEG lipid, a phospholipid, and cholesterol. Now, the phospholipid and cholesterol are generic and pretty much similar across LNPs. The two differentiating factors really are the ionizable lipid and the peg lipid. And the ionizable lipid is probably the most critical in terms of determining the potency and the safety profile. So this is a chemical structure, ionizable lipid. And, for VERVE-101, we in-licensed an ionizable lipid from a company called Acuitas Therapeutics. And then the PEG lipid was also licensed in from Acuitas. So that's our 101. For 102, the PEG lipid is ionizable lipid is different. The PEG lipid is different. The ionizable lipid is licensed from Novartis. And the PEG lipid is a commercially available PEG lipid called PEG-DMG 2000. So those are two key differences between 101 and 102. There's also one additional difference: we added a targeting ligand to 102, a GalNAc carbohydrate that is anchored to the surface of the lipid nanoparticle. Remember, the lipid nanoparticle, you have the cargo in the middle, the mRNA and the guide, and then those are negatively charged. And then this little fat bubble, the lipid nanoparticle, envelops the cargo. And we've anchored to that little spherical bubble a carbohydrate that comes out onto the surface. And that carbohydrate is GalNAc. It's a proprietary GalNAc. There are other GalNAcs out there initially developed by Alnylam, for example, that's conjugated to nucleic acids. But this is our own proprietary GalNAc. So the GalNAc LNP is really our 102 with those components. When you think about your preclinical data sets that you've had for VERVE-101 and you've developed for VERVE-102, how do they compare? And I guess maybe what is the level of confidence that that gives you as you think about this Heart-2 study? Yeah. So, there are two items that would give us a lot of confidence regarding 102. First is the ionizable lipid that's used that's being used, that's licensed in from Novartis, has already been tested in third-party clinical trials, over 100 patients dosed. And that ionizable lipid has been well tolerated, and with good efficacy. So that human data gives us confidence. And second, in our own preclinical data with 102, we see that we, you know, with 101, we saw the ALT changes, and the platelet drops, at very high doses, doses higher than the no-observed adverse event limit for 101. For 102, we don't see any pronounced platelet drops at any dose that we give. And the LFT changes are much milder. Our own preclinical data in non-human primates gives us confidence as well as that human data that I mentioned. Got it. And now with the initiation of Heart-2, just help us think through what the trial design looks like. Have you disclosed what doses you're looking at there? How comparable are those doses to what you were looking at with 101? They're comparable doses. We haven't disclosed the exact doses in terms of public guidance. The study design is basically a single ascending dose design, a few patients at each dose level, roughly three-nine. It's flexible, adaptive design. The goal is to identify the dose where we get good efficacy and, of course, without the safety signals. In terms of the patient population we're studying, it's a little bit different than 101. It's expanded. We have the heterozygous FH group, which is the patients with the genetic form of high cholesterol from early in life, about 3 million patients in the U.S. and Europe with HeFH, heterozygous familial hypercholesterolemia. We've also added a group called premature coronary artery disease. This is just a fancy term for anybody who's young who's had a heart attack. The age cutoff we are using is men less than 50, women less than 60 with a heart attack. This is actually a large. This is about 20% of all heart attacks in the U.S. and Europe. So we've added those two groups are being studied. The reason we chose those two groups is, again, going back to our key differentiator, which is lifelong LDL lowering. So we wondered, who are the people that need not only, you know, it's like the how low versus how long, who needs deep LDL lowering for decades? So if you've had a heart attack at 35 or 40, you're looking at like 30 or 40 years of daily pills. That's just not happening right now. So I think those patients would be, you know, particularly benefit from a one-time therapy that has durable effect, as well as the patients who have HeFH. When can we expect first data here? We're guiding to data in 2025. As the year goes on, we hope to be able to narrow that guidance in terms of further, within 25. Are you still committed to, I mean, I guess maybe evaluating VERVE-102 against VERVE-101? How should we think about your strategy to bring one asset forward? Yeah. If you recall, when we chatted last year, we explicitly laid out the strategy of having two product candidates that differed only in the delivery system because we knew that delivery was one of the key risks for the whole field. There's only been one example, really, before us, Intellia, that had taken from, you know, from preclinical data to humans for in vivo gene editing in terms of delivery. So we knew that delivery was a risk. So we had two product candidates. Our goal was to evaluate both in the clinic, pick one to go forward to phase two in 2025. That timeline is still entirely on track. Nothing's changed there. You know, what we want to see now is the 102 data. But with 101, the main thing would be, can we develop a mitigation measure that would avert the laboratory abnormalities? If we can, there very well may be a path forward for 101. What types of mitigation strategies are on the table here? I mean, I think that, you know, the typical ones you'd think about for this kind of thing would be concomitant medications that might dampen the AEs. The other would be some sort of, you know, we always call our medicine single-course treatment, and what is meant by that is, you know, you could imagine taking the required dose and splitting it into two doses and being given, let's say, 30 days apart, you know? And that's often a strategy to keep the efficacy but take away the safety profile, particularly if the safety profile is driven by, let's say, Cmax or even a, you know, even area under the curve, because when you split the dose and divide it in half, you're going to have less given during that time and hopefully less safety signals. Now, we've already shown in preclinical models that you can split the dose and give it 30 days apart in non-human primates, and you actually get stacking of efficacy after the second dose in terms of editing in the liver. But you don't actually have any more safety signals from either dose. So that strategy would be another option. And would you, I guess, maybe look to evaluate that strategy of the stacking or the multi-dose before you make a decision on VERVE-102? I don't think so. If VERVE-102 has the profile that we're looking for, let's say the same efficacy as 101, but no safety signals, then that might do the trick just to move forward directly from Heart-2 trial. Got it. And with VERVE-102, remind us, that is being conducted ex-U.S. Are there plans to file an IND here in the U.S., or where does that stand? Yeah. I think the key thing for us is that with 101, we got an IND cleared. That IND is, you know, we now know what it takes in terms of the FDA for in vivo base editing, the set of requirements. And so we're going to kind of keep that in our back pocket. And basically, for 102, it's really about where can you most efficiently enroll, and then, you know, take that data, and move it forward in terms of a global regulatory strategy. So for IND for 102, current plans are really with phase two. What does that phase ll trial look like? The phase two, so the key thing between phase one and phase two is adding a control group. So phase one is an open-label trial without a control group. So everybody's getting treated. And, you know, that's appropriate for a SAD design. But I think for phase two, we're going to want to have a group that gets kind of placebo infusion. And besides that, it'll probably be one or two doses. So the goal, of course, is to pick an effective and safe dose for larger phase threes. And I think the inclisiran development program is a reasonable benchmark for what you're going to expect from us from phase one, phase two, and phase three for HeFH. Their program, remember, that modality, siRNA for cholesterol, was brand new just a few years ago and had some of the same concerns or questions that people are asking now about it's a new new treatment modality. There are already pills available. There's already antibodies. Do you need something else? And so forth. But, you know, you saw that they developed with a phase l and phase ll with a control group. Then their phase lll for heterozygous FH was about 500 people, with half treated, half control. What is your latest thinking on the need for a cardiovascular outcomes trial? Yeah. For heterozygous FH, there's never been a cardiovascular outcomes trial required or completed. I think all approvals to date for the pills, the antibodies, the siRNA for cholesterol have come based on LDL as the endpoint. That's our expectation as well, for this modality. Now, I think we may end up pursuing a cardiovascular outcomes trial, you know, for more for market adoption, and commercial. But it we don't think it'll be required for registration. Got it. We've also talked about in the past, Verve's goal of going after three different pillars of lipoprotein risk. Remind us maybe the rationale behind that. What is the latest thinking on maybe what is the best or the most appropriate target to go after to really be able to reduce that risk and to think about the development of that? Yeah. So, you know, I mentioned that the answer to heart attack is getting the cholesterol as low as possible for as long as possible. I'm talking like 50 mg/dL lifelong. If that's the case, very hard to get a heart attack. Cholesterol is carried in any of three different particles. One is LDL, low-density lipoprotein, and that's called low-density lipoprotein cholesterol. There's a second set of particles called remnant particles, also called triglyceride-rich lipoproteins. And the cholesterol carried in those particles is called remnant cholesterol. The third particle is called lipoprotein(a), and that's lipoprotein(a) cholesterol. So we want to have a product ultimately that attacks each of these three carriers of cholesterol in the blood. Our PCSK9 target attacks LDL. Our ANGPTL3 program attacks LDL and that remnant cholesterol, remnant particles. And then the LPA program attacks the third group, lipoprotein(a). Overall, PCSK9 and LDL is the dominant factor for everybody. But in some patients, there's remnant can be a problem as well. So that's why we have that second option. And then in a smaller fraction of patients, LPA is the main driver. And so we have that third option. That's a great segue to 201. Maybe give us an update there on where you stand. And you've talked here about the rationale for targeting ANGPTL3. But, any more details you can provide? Yeah. I think the ANGPTL3 program, you know, our setup, in terms of the next 18 months, 12-18 months, you know, it's very. Our whole platform is very modular. Our pipeline is modular. Once we de-risk the delivery system, you can just switch out the cargo, and then you have a series of products. So the GalNAc LNP is a delivery system that's being de-risked right now. Right now, it's carrying PCSK9 guide RNA and the mRNA for the base editor. The second product is the same GalNAc LNP and the same base editor, but a different guide. The guide now targets ANGPTL3. ANGPTL3, if you turn that gene off, you lower cholesterol in a way that's independent of PCSK9. So it's additive in effect to PCSK9. And it works in a group of patients called homozygous FH. This is a rare orphan disease. So this is our only indication of, in terms of our pipeline that is a rare orphan disease. And that has particular advantages here because the registration here for an antibody targeting ANGPTL3 occurred with about 60 patients of data. So we think we can develop the 201 program into a functional cure for the LDL component of the homozygous FH patients with 201 with a much smaller study, possibly as low as 50-60 patients. And this might be our first product to market, actually. Now, on top of the homozygous FH patient population, this product could be added to another group called refractory hypercholesterolemia. These are patients who have high LDL despite statin plus PCSK9. So this could be the second the next group. That's a pretty large group of patients, about 7% of all patients with, with heart disease, coronary heart disease. So that's our second product. The third product, I think we can talk about now maybe is lipoprotein little a. And here, this is a partnership with Lilly. And I think this gives me a chance to kind of, talk a little bit about that relationship. So for this product, LPA, we are doing the research. Lilly is paying for all the research. and we we take it through phase one, and then the program transferred over to them. And then at that point, we get royalties and milestones in this case, but we can also opt in for a profit share. So that's the LPA relationship with Lilly. We do have a relationship with Lilly for our first two programs as well, ANGPTL3, and they could potentially be a partner. But there, for those two rights, okay, that's what Lilly holds. What I mean by that is both of them. But at the end of phase one, they have the ability to opt in. Then they pay for a third of worldwide development costs. In return, they get 50% of U.S. profits. The other 50% of U.S. is owned by Verve, and 100% of ex-U.S. is owned by Verve, and we control development, and we book revenues for those products. So Lilly owns minority rights, for PCSK9 and ANGPTL3. Now, we're super excited to have Lilly as a potential partner for all three of these programs because, you know, this is really cardiovascular disease, and there's a, you know, they have a lot of expertise in development in cardiovascular disease, and that they really are aligned with us, that the next big thing to do in cardiovascular disease is not go after new targets, but rather pick the existing targets of high conviction and develop a new treatment modality, a one-and-done option against each of those. So that's what's happening with us. So when you think about your Lilly partnership, I mean, that's a great example where the structure of that partnership or the type of work is different across the different programs. How do you think about the strategy when you're contemplating how best to move forward with a partner? What goes into that decision-making process? Well, I think the Lilly and the Vertex, those are the two major partnerships we have, going to give you a sense of, how we choose partners. I think Eli Lilly is probably no better company in the world right now to work with, for cardiometabolic disease, for a range of reasons that people are, familiar with. Now, Vertex, that's a collaboration where we're focused on not on cardiovascular disease. That's actually the only, product in our pipeline that is liver disease. And we chose to work with them, because they have deep expertise in this disease. They're really a wonderful partner. And that structure is very much like the LPA structure where they're paying for all the research now through phase one, and then we have the ability to opt in again. We transfer over to them after the end of phase one, and then we can opt in for a profit share if we choose to do so. Different structures based on the company, based on the targets, based on what we can bring to the table versus what the other party can bring to the table. Then we touched on a little here. You mentioned base editing, but there's obviously a number of other strategies here within genetic and genomic medicine and editing. How do you think about the capacity of your platform? Very focused. So we're really focused on generating product, typically in cardiovascular disease. And so we're very technology flexible. And you can see that in our pipeline. You know, we are open to different editing technologies. We're open to different delivery technologies. We simply want to make the best product possible. In terms of editing, you know, we're using base editing for our first couple of products. But you can see that we're developing our own bespoke editor for the LPA as well as the program with Vertex. So it just reflects, I think, the team that we've built and our focus to develop to address unmet needs. Maybe in the last couple of minutes here, as you look forward over the next 12-18 months, what should investors be sure to take note of? Well, I think I think it's an incredibly exciting time. You know, we're on the cusp of de-risking the delivery system. And as I mentioned, really, spring-loaded for success in terms of, the additional cargo can be switched out. And we have a robust pipeline to address atherosclerotic cardiovascular disease in a very systematic way. LDL cholesterol, remnant cholesterol, lipoprotein(a) cholesterol. And these are huge markets. You know, there's about 50 million people within the U.S. and Europe with ASCVD. There's a couple of million people with the heterozygous FH. And so as I mentioned, there's a huge unmet need, despite the fact that there are available treatment options. And I'll come back to that, the couple of misconceptions. One is this idea that, you know, the treatment is $ millions a dose and how will people end up paying for it and so forth. And I don't think, you know, we're going to be that. We don't have to be that because I think our products will ultimately look more like one-time medical procedures in cardiovascular disease that are paid for every day right now, by Medicare, by commercial payers and so forth. So there's a path already. So I think that it's an exciting next 12-18 months for us as we move through the SAD phase and de-risk the delivery system. Great. Maybe one last question. Just remind us on your cash runway. Where does that get you to? Yeah. So we ended Q1 with about $606 million. This gets us to late 2026, if not into early 2027. And, I think that runway gets us phase 1 data for 102, phase 1 data for 201, and then further progress on LPA. You know, we received our first milestone payment from Lilly for LPA product that reflects our progress. And so we'll continue to make progress there. And so those are the key inflection points, I think, within this budget envelope. Awesome. Well, with that, thank you so much for joining us. Thank you, everyone. Thank you.