Welcome, and thank you for joining us today for our discussion of the interim results from the Heart-1 trial of VERVE-101. I'm Jen Robinson, Vice President, Investor Relations at Verve Therapeutics. Before we begin, I would like to remind you that any statements we make at this meeting that are not historical facts or are forward-looking statements reflecting the current beliefs and expectations of management, made pursuant to the Safe Harbor Provisions of the Private Securities Litigation Reform Act of 1995. Examples of forward-looking statements made during this meeting include statements regarding the safety, tolerability, and potential benefits of VERVE-101, the company's clinical development plans, and the company's strategic plans and prospects. Forward-looking statements during this meeting involve substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by the forward-looking statements, and we cannot assure you that our expectations will be achieved. Such risks and uncertainties include those set forth in our most recent quarterly report on Form 10-Q, as well as our other current SEC filings. We assume no obligation to update or revise any forward-looking statements. Following this meeting, a replay will be made available on the company's website, www.vervetx.com. Today, we'll be joined by Dr. Sekar Kathiresan, our Co-founder and Chief Executive Officer at Verve Therapeutics, Dr. Deepak Bhatt, Director of the Mount Sinai Fuster Heart Hospital, Dr. Andrew Bellinger, our Chief Scientific Officer, and joining for Q&A will be Fred Fiedorek, our Chief Medical Officer, and Allison Dorval, our Chief Financial Officer. With that, I'll hand the mic over to Sek. Okay. Thank you, everybody, for joining us tonight. What is really, we think a milestone event for hopefully for cardiovascular medicine. It's early, but I think the data that we just presented earlier today potentially points the way in terms of a whole new way to treat heart disease, and we're super excited about that. Today, we'll be covering the disease process, our mission and vision, and then moving on to VERVE-101. We'll go through the results again, and then give you some updates in terms of our pipeline, the recent progress, and then we'll close with some Q&A. Thank you again. Okay, Verve is focused and well-positioned to realize its vision of developing single-course gene-editing medicines to treat atherosclerotic cardiovascular disease or ASCVD. What you'll hear tonight is that we have human proof of concept for in vivo-based editing technology. We have three product candidates against highly validated targets. We have now an emerging path, regulatory path, in the U.S. with our recent FDA IND clearance for VERVE-101. We also have a new partner, a terrific partner in Eli Lilly, with a shared vision, cardiovascular development, expertise, and strength in commercialization of products in this space. Finally, we're well-capitalized with about $485 million in cash and runway into 2026. So really an exciting path forward. I'm going to turn it over to Dr. Deepak Bhatt, who's going to walk through the disease indication of heterozygous familial hypercholesterolemia and the unmet need in this indication. Dr. Bhatt? Well, thank you. It's really wonderful to be with you all at this event, and really like to congratulate Dr. Kathiresan. We've been colleagues at Harvard Medical School for many years. It's terrific to see you in this role and the success of Verve. The scientific breakthrough today, I think, was tremendous and, you know, something that one day might win a Nobel Prize. So really great to, in some small way, be part of it here. Dr. Bellinger, who I worked with closely for many years at Brigham and Women's Hospital, wonderful seeing you now on the big stage shining, just really makes me happy. Before I get started on my topic for today, disease indication, unmet need, just in terms of disclosures, I don't have any financial relationship with Verve. Although, after today's date, I wish I did, but I don't have any financial relationship with them. I do receive research funding from Amgen and from Novartis and Sanofi for clinical trial work on those PCSK9 inhibitors that they make, as well from Lilly, having to do with tirzepatide and clinical trial work I do on that, diabetes and obesity drug. So, there's a huge unmet need here. By here, I mean in the U.S., I mean in the world. ASCVD, atherosclerotic cardiovascular disease, remains the leading killer. That's true in the U.S.; it's true worldwide. There are hundreds of millions of patients worldwide with atherosclerotic cardiovascular disease. Still, one person dies every 34 seconds from cardiovascular disease in the United States, and there are about 800,000 heart attacks per year in the United States, so still a big deal. You hear a lot about advances in cardiovascular disease. It's true, but there's still an unmet need that's enormous. I don't know if you've all heard of these concepts of secondary prevention, that's taking care of people that have had, for example, heart attacks. Primary prevention, that's treating risk factors like hyperlipidemia that can lead to heart attacks. And primordial prevention, preventing the development of the risk factors in the first place. And as a cardiologist, you know, I spend a lot of my time in the secondary prevention universe, treating existent identified disease and primary prevention, treating risk factors. But imagine if we could really-... Frame shift things to primordial prevention, to actually get to patients before they become patients, to treat them before they actually develop the risk factors that lead to cardiovascular disease. I think the technology we're gonna hear about has that potential. Maybe some of you with a medical background have heard of pack years of smoking. That's the number of packs per day a person smokes, times the number of years. So if somebody smokes a pack a day for 20 years, that's 20 pack years of smoking. The higher the exposure, the worse. This is a concept that's similar, but for cholesterol. Cholesterol years for cardiovascular risk prediction and treatment. And the point that it's trying to make here in this graphic is that if a person has really high cholesterol, such as from familial hypercholesterolemia, where the cholesterol is elevated right out of the gate from birth, well, that's a problem because they're exposed to those very high cholesterol levels for a long time. But actually, even if someone has more moderate degrees of elevated cholesterol, but has additional cardiovascular risk factors, or has actually had a heart attack that they survived, well, there as well, there's a lot of risk. And the amount of time, the number of years they are exposed to the cholesterol elevation, just how high the cholesterol are, that combination essentially gives you an area under the curve, and the higher, the worse it is. And again, potentially, if we can intervene early enough in this cycle, we might be able to put a real dent in the cardiovascular epidemic. Now, does LDL cholesterol matter? Hopefully everyone here is convinced that it does, but just in case there are any skeptics, these are some data. It's from the ODYSSEY OUTCOMES trial, but there are other sources of data that show similar findings. We see that lower is indeed better. The lower the cholesterol is, the lower the risk of dying. And where things seem to sort of plateau is maybe around the 20-ish to 30-ish range, sort of the cholesterols, the LDL cholesterols of a newborn baby. That's a normal cholesterol. That's a natural cholesterol. The cholesterol that I have, that everyone on this panel has, I bet most of the people here, unless you're on medicine, is an abnormal cholesterol. We're all walking around with abnormal cholesterol, and some folks are walking around with really abnormal cholesterol. What's going on in the U.S. in people with coronary artery disease? I'm talking about U.S. adults, they have coronary artery disease. There's no debate about it. Well, in this recent publication from JAMA, we're looking at the NHANES registry, and it turns out that only 1 in 4 folks, if you use the American guidelines, where the target for cholesterol should be less than or equal to 70 milligrams per deciliter, are actually achieving it. And if you use the European guidelines, which I like a little bit better, that say the target should be less than or equal to 55 milligrams per deciliter, only 1 in 10 green people. Everybody else there is red. So that shows that right now, in the United States, in people that have identified coronary artery disease, we're doing a lousy job of treating cholesterol. The combination of the healthcare system, doctor, and patient isn't working. And there are a lot of reasons for this. Some of this has to do with poor adherence to therapy. It's tough to take a pill every day. There are a lot of reasons that this is the case, but it is the reality. And this is why people, even with identified coronary artery disease, go on to have recurrent heart attacks, sometimes recurrent fatal heart attacks. This is a Mendelian randomization study. Maybe it's a little too late at night for this, but this is basically nature's way of randomizing patients to different genes at birth and then seeing what happens. What this study shows is that both genes that control LDL cholesterol and genes that control triglyceride-rich lipoprotein are associated with cardiovascular risk, such that lower is better in both cases, and independently so. This really gets to the point that LDL cholesterol is really important, often the focus of atherosclerosis treatment and prevention, but triglycerides matter, and in fact, other things matter. This is the concept of residual cardiovascular risk. We really wanna target cholesterol, get that as low as possible if it can be safely achieved. Probably also inflammatory risk, thrombotic risk are important, triglyceride-associated risk, Lp(a)-associated risk, and diabetes-associated risk. Targeting all these different pathways can, in fact, have an enormous impact on that residual risk and hopefully prevent recurrent cardiovascular events. And in doing so, we can potentially put a dent in this pyramid of risk, where we can hopefully move patients from, say, the primary prevention universe, from going into the secondary or tertiary prevention universe, where they have a heart attack or a fatal cardiovascular event. And maybe in the distant future, even intervene early enough in the primordial prevention stage to keep patients from developing that risk factor in the first place. So lots of potential when we're talking about therapies like gene editing. Finally, I'm just gonna say a word about heterozygous familial hypercholesterolemia. It's a serious inherited subtype of atherosclerotic cardiovascular disease with very high LDL cholesterol levels from birth and heart attack at early ages. Just working from left to right, on this slide, you can see what characterizes familial hypercholesterolemia. It's a high LDL cholesterol, a family history of high LDL cholesterol or premature atherosclerotic cardiovascular disease. People having a heart attack at an early age. It can be monogenic or polygenic. The LDL cholesterol is often greater than equal to 190 milligrams per deciliter. That's in a lot of definitions of it. An ischemic event, like a heart attack or a stroke, often manifests in these folks and age 30 to 60, in that range, sometimes earlier, sometimes even later. There are a lot of people that are affected, at least 3 million adults in the U.S. and Europe. I think this is a bit of an underestimate, but at least 20 million people globally. This is a real problem, and heart attacks obviously are a bad thing. That's an obvious statement to make, but these are premature heart attacks that we're talking about. So we're talking about people that in the prime of their lives are being taken. So anything that can address this problem effectively could be a really huge advance. And with that, let me turn things back over to Dr. Kathiresan. Thank you very much, Deepak. Okay, let me walk you through a little bit of the background in terms of Verve's mission and vision. So we start by asking this question: What causes ASCVD? And as Dr. Bhatt highlighted, the key cause is high cumulative lifelong exposure to blood cholesterol clogging the heart arteries. And cholesterol in the blood is carried in any of three different lipoproteins, LDL, low-density lipoprotein, triglyceride-rich lipoproteins, that's TRL, or Lp(a). So these are the lipoproteins that carry cholesterol in the blood and ultimately cumulative exposure to this cholesterol clogs the heart arteries. Now, what's the solution? The solution has been highlighted by human genetics, and the solution is to keep blood cholesterol as low as possible for as long as possible. How do we know that? Because there are people who are walking around who have certain genes switched off. In one case, PCSK9, naturally switched off, leading to lifelong low levels of LDL cholesterol and resistance to ASCVD. In the case of PCSK9 deficiency, natural deficiency, it's about 50 mg/dL lower LDL in the blood in those individuals, about 50% lower risk of ASCVD, and importantly, absence of this gene or deficiency of this gene, either in one copy or both copies, the individuals are healthy otherwise. So this gene is more or less a spare part. You can get rid of it, and all you get is health. So these observations led us to wonder, what if we developed a medicine that would mimic those natural resistance mutations? Now, there are a number of pills and injections available right now to lower LDL, right? So we often get asked, "What's the unmet need?" Well, if you look at patients with heterozygous FH, only about 3% of patients worldwide with HeFH are at LDL goal. So we know that we need to get the LDL as low as possible for as long as possible. We have several medicines available right now to do that. So why is it that the majority of patients actually are not at goal? And we think a lot of that has to do with the chronic care model to treat HeFH and ASCVD. This model involves daily pills or intermittent injections, administered often over decades, and that puts a heavy treatment burden on patients, providers, and the healthcare system, and that model really does seem broken. If you think about that model and apply it to a typical patient with HeFH, this is what it might look like. On the x-axis is age, on the y-axis is the level of LDL cholesterol. You can see here the patient's LDL is about 200, starting at birth, and the patient has a heart attack at age 44, so premature heart disease. Typically, the patient gets a procedure, maybe a stent to clear the clogged artery, and then will get put on therapy to lower LDL. In this case, you can see they get put on statins and ultimately a PCSK9 antibody. LDL does come down, but doesn't usually stay down. There's oscillation in the LDL over time because of issues related to the chronic care model. The patient adherence, access, healthcare infrastructure issues, and that lack of control of the cumulative exposure leads to recurrent heart disease events, and those are shown at the top. Another stent, bypass surgery, or sometimes even a fatal event. So what we'd like to do is replace this picture with this picture. A one-time therapy, dramatic and durable lowering of LDL to really control LDL over a lifetime. Now, as I said earlier, this is a significant milestone today for Verve, with the interim data that Andrew presented earlier today, really provides proof of concept in humans for in vivo liver base editing. And this is the timeline, kind of how we got to today. Verve was founded in 2018. In 2020, we developed proof of concept for in vivo liver base editing in non-human primates. Last year, we dosed our first patient with VERVE-101, and today we presented the interim data that we'll discuss a bit more in a few minutes. Let me walk you through the preclinical data that allowed us to start our first human tests. This is VERVE-101. It's a novel base editing medicine designed to inactivate the PCSK9 gene in the liver and lower LDL cholesterol with a single DNA base pair change without cutting the DNA. The drug substances are shown on the left. It's two molecules, mRNA for ABE base editor, and a guide RNA that localizes the editor to the PCSK9 gene.... Both of these drug substances are packaged in a lipid nanoparticle, which is shown in the center, the components, and then the drug is schematized all the way on the right. VERVE-101 is delivered as an intravenous infusion. I'm going to walk you through the mechanism of action. So number one, delivery by single IV infusion into the blood. The lipid nanoparticles are taken up from the blood by hepatocytes through the LDL receptor, and that's what's shown in the middle. Once inside the cell, the adenine base editor mRNA is translated to protein. The protein binds to the guide, the complex of the guide, plus the protein, make their way to the nucleus, ultimately scan the genome, chromosome by chromosome, to land at the directed spot. For us, that's in the PCSK9 gene on chromosome one. So there's localization of the base editor to the PCSK9 gene sequence on chromosome one. Then at that spot, there's a single spelling change made, an A to G to turn off the gene, again, without DNA cutting. That A to G change is in the canonical splice site, in between exon one and intron one. Turning off the gene, of course, will lead to decreased production of PCSK9 protein, which ultimately leads, should lead to reduction in the blood LDL cholesterol. We've done extensive preclinical evaluation of VERVE-101 in non-human primates and human, and human cells to document the efficacy in terms of protein reduction and LDL reduction, the durability, a liver-specific biodistribution, as well as absence of detectable off-target editing. Here's the durability data. Durability out to now 2.5 years in non-human primates after a single dose of VERVE-101. The x-axis here is time, on the y-axis is the LDL reduction in two groups of animals, control, as well as VERVE-101 treatment. And you can see there's about a 60%-65% reduction in LDL that is durable, at, that starts at two weeks, durable out to 2.5 years after a single treatment. This is the liver-specific biodistribution in non-human primates treated with VERVE-101. On the x-axis are tissues at necropsy in several groups of animals. On the y-axis is the level of PCSK9 editing, and what you can see is there is very high level of editing in the liver and really very little in any other organ. There's a little bit in adrenal and spleen, but that's, that's about it. So this is a liver-directed therapy, liver-specific biodistribution. Lastly, we've done extensive work on off-target, and here's just one data slide on that. On the x-axis here are a range of chromosomal locations, so about 6,000 different potential off-target sites. On the y-axis is a level of editing in human liver cells treated with VERVE-101. So these are liver cell, liver cells in a dish treated with VERVE-101, and there's no evidence of off-target editing. You can see on the x-axis, all of the potential off-target sites in black are basically centered around zero, and you have editing at the PCSK9 spot on chromosome 1, the large purple dot. These are data, again, for single base pair changes, potentially of on-target and off-target sites, and you're seeing exquisite on-target editing only. There's also another type of off-target event that people look at, and those are larger changes beyond single base pair changes. So these are chromosomal translocations or structural variations. So these are large pieces of DNA that rearrange, could potentially rearrange with treatment. Shown here are data looking at chromosomal translocations or structural variants after treatment of primary human liver cells with VERVE-101. The first circle is untreated, and what you can see, the red dots and the various dots, also the green lines, represent different types of structural variations in this donor. So these variations exist in all of our cells. So that's there. Then you get VERVE-101 treatment in the middle, and then... And finally, all the way on the right is treated minus untreated. And what's important to note is there's treatment does not generate any new structural variation. All the way on the right, you're not seeing chromosomal translocations or other types of events, like insertions or duplications. This is something you see with base editing, the absence of chromosomal translocations or structural variants, something you typically don't see with standard CRISPR-Cas9. Standard CRISPR-Cas9 typically leads to a low rate of chromosomal issues of the sort that are shown on the left. Okay? So these are... These data are part of the reason why we eventually chose base editing for our first few programs. We directly compared standard Cas9 with base editing in cells, mice, and non-human primates before selecting base editing for our programs.... Now, with that as background, let me turn it over to Andrew to walk you through the study design as well as the interim results. Okay, thank you, Sek. So the Heart-1 trial is a Phase Ib trial of VERVE-101 in patients with heterozygous FH. It's open label, single ascending dose design with flexible and adaptive dose levels, with about 3-6 patients in each cohort. Today, we are able to share the interim update with 10 patients dosed across 4 dose cohorts. We have 9 patients treated at 0.1, 0.3, and 0.45 mg/kg, and 1 patient dosed in the 0.6 mg/kg cohort. The data cutoff date for this presentation was October sixteenth, and the study is continuing to enroll and accrue more data. I think it's really important to pause on the decision of what kind of patients to enroll in a Phase I study. So you may be familiar with a lot of the Phase I studies that were run for siRNAs or monoclonal antibodies, where typically you run a Phase I study in healthy volunteers. The FDA issued this guidance in 2022 that for gene genome editing products, they recommended that subjects with severe or advanced disease would be most appropriate for first in human gene editing trials. And they actually also called out that these patients, however, may be more predisposed to experiencing adverse events or to be receiving concomitant therapies that make it difficult to interpret safety. Now, we were guided by this guidance in choosing to enroll patients with severe advanced heterozygous FH, and that was a very conscious decision. What you see here is the study design. The study population is males and females, 18-75, with heterozygous FH, established atherosclerotic cardiovascular disease. That means they have atherosclerosis, they've had myocardial infarctions or strokes. They have uncontrolled LDL cholesterol that are not at goal, and that's despite maximally tolerated oral lipid-lowering therapy. The drug is administered with a pre-medication regimen of steroids and antihistamines that has been established in the field from other lipid nanoparticles, and it's administered as a single infusion via peripheral IV. The endpoints were safety and tolerability, pharmacokinetics of VERVE-101, and blood PCSK9 and LDL-C values, which we measured as a time average from day 28 onward. The study duration is one year, with an additional long-term follow-up study that patients roll over into per guidance from FDA and European regulators. So the participants enrolled to date, the 10 participants, have had severe advanced ASCVD and a high risk for cardiovascular events. Their mean age was 54. Their mean screening LDL cholesterol was 193. That's on treatment. Their nine out of the 10 had a mutation in their LDL receptor. The majority of them, nearly all of them, have had prior coronary revascularizations. These include both coronary artery bypass grafting and prior PCIs, in some cases, multiple PCIs. And about half of them had had a prior heart attack as well. One of them had had a prior cardiac arrest as well. Most of them, nearly all of them, were on a statin therapy. None were currently on a PCSK9 inhibitor, which was an exclusion for the study, but two had been previously on a PCSK9 inhibitor. The results are on the next few slides. We saw dose-dependent reductions in PCSK9 following treatment across the 4 dose cohorts. There was minimal effect at the first 2 dose levels, but very dramatic reductions in PCSK9 at the higher 2 dose levels, 47%, 59%, and 84%. I think it's important to say that when you look at the PCSK9 in the blood, about 85% of it comes from the liver. The other 10%-15% comes from other organs. We're only editing the liver, so we expected an upper bound on the PCSK9 reduction of about 85%-90%. So in that patient where we saw 85% reduction, that suggests that we were able to edit nearly every hepatocyte and make a single base pair change in both copies of the PCSK9 gene in that individual. Looking at the LDL reductions, we saw clear dose-dependent reductions in LDL cholesterol following treatment. The reductions in the higher two dose cohorts were 39%, 48%, and 55%. These are again presented as time-weighted averages after from day 28 onward through the follow-up. The bars here are by cohort and cohort average, and each dot represents each patient, suggesting that the result here looks very consistently dose responsive. I just want to pause on this to show, to say that this is the first evidence-... of in vivo gene editing, having a clinical benefit for patients in LDL lowering, which is, as you know, a surrogate endpoint accepted by the FDA as a clinical endpoint. This is the data looking at durability. On the x-axis here is time in days. On the y-axis again, is percent change from baseline and LDL cholesterol. The lines are for each of the dose cohorts. The number of participants in each is at the bottom. And you see that the dose reduction, the LDL reductions that we're seeing are durable. There's a 55% reduction at day 28 in the patient, the participant patient at 0.6 mg per kg, and that has been rock steady out to day 180, 55% reduction in LDL cholesterol. Now, this is very consistent with the preclinical data that we've seen, where we saw reductions of LDL cholesterol being durable out to 2.5 years. Turning to safety, the observed adverse events were largely consistent with the severe advanced ASCVD patient population that we enrolled in the study. So I'm going to focus on a few different aspects. Looking at the adverse events that occurred in more than one participant, the infusion reactions were common at the higher doses, not at the lower doses. These were typically mild headaches, body aches, fever, and resolved within a few hours. And these were largely expected based on prior lipid nanoparticle experience. COVID and upper respiratory infection was the only other adverse event to occur in more than one participant. On the serious adverse events, we saw the two cardiovascular serious adverse events that we'll talk about in another slide. We saw no non-cardiovascular serious adverse events, and this was really, I think, a key point for us as we were thinking about this study, where we did expect cardiovascular adverse events, but we're looking at the non-cardiovascular events. Any treatment-related AEs Grade 3 or higher, increased liver transaminase we saw in one participant at 0.6 mg/kg. We'll show you that in a second. Again, transient reversible, and then the cardiovascular event that we'll talk about. So these are the ALT elevations on the left. They are dose responsive, they are transient, they are asymptomatic, and they recover within about two weeks to baseline. These are essentially the same as what we had seen non-clinically in non-human primates, and based on our discussions with KOLs and other experts on the FDA's advisory committees, for a one-time therapy, we thought this was gonna be not an issue. There is no bilirubin changes on the right, reassuringly. So about those serious adverse events. You know, we enrolled patients who had advanced coronary disease. The first participant who had the fatal cardiac arrest had an ischemic cardiomyopathy and had a prior cardiac arrest. The autopsy showed severe underlying coronary artery disease as the cause of death, with no evidence of pulmonary embolism, myocardial inflammation, or coronary thrombus. The investigators in DSMB reviewed this case carefully and deemed it unrelated to study treatment. In the second patient, there was an MI and non-sustained ventricular tachycardia. So this patient had a fairly complex cardiac history of having multiple prior interventions and multiple prior heart attacks. This patient, in particular, had had a, an unusual form of coronary disease called, in-stent restenosis. So this is where you put a stent into a blockage, and then smooth muscle proliferation happens inside the stent. This is different than the typical plaque that builds up in coronary arteries. It's smooth muscle constriction of the vessel. This patient had severe in-stent restenosis that had recurred three times. Recurrent treatments had been unable to resolve it. Patients with in-stent restenosis have very high risks of, adverse events, MACE events, over one year. In some prior studies, as high as 30% or more. On coronary angiography, this patient had critical left main equivalent coronary disease with in-stent restenosis lesions in both the LAD and circumflex, which were felt to be preexisting, prior to treatment of course. And in particular, this patient, it turns out, you know, and this is unfortunate in a clinical trial, of course, had been having unstable symptoms that had not been disclosed to the investigators, prior to treatment. The investigators in DSMB reviewed the case with us and, determined that the MI was potentially related, largely related to the proximity to dosing. The NSVT was unrelated, and recommended that we continue dosing with no required protocol changes. So what are the next steps? We are actively enrolling in the 0.45 and 0.6 mg per kg cohorts to complete the dose escalation phase. We have active sites in New Zealand and the U.K. With the IND clearance in the U.S., just a few weeks ago. We are working to activate U.S. sites to participate in the study as well. Our plan is to complete this ascending dose phase and then enroll an expansion cohort in 2024. And then based on a comparison of the composite data between this program and the VERVE-102 program that we'll talk about in a minute, initiate a randomized and placebo-controlled Phase II study in 2025. So in conclusion, I think what we saw today is that we demonstrated the first proof of concept for in vivo DNA-based editing in humans. We saw dose-dependent reductions in blood PCSK9 and LDL-C following VERVE-101 infusion. The LDL-C reductions were clinically meaningful: 39%, 48%, and 55% among the patients in the two higher dose cohorts. We have durability data out to six months in the patient in the highest dose cohort. Obviously, we'll be continuing to follow those patients for years to extend that durability, and based on the preclinical data, we have every reason to believe that that durability will extend potentially for a lifetime. The safety profile was, you know, supports continued development of VERVE-101 and was largely consistent with what we expected in a Phase I study in these high-risk patient populations. So, we're—we are very excited to expand the inclusion criteria as we move forward to enroll more patients and build the data set behind VERVE-101. I think Sek... Oh, and of course, I should say thank you to, most importantly, the patients and their families who volunteered to participate in a very novel gene editing trial for their heterozygous FH. And also to the investigators and staff who've been working with us on this study and calling out, I think, in particular, the NZCR group in New Zealand and the Richmond Pharmacology group in London, who've been terrific investigators to work with, and also to a really strong DSMB, who's been very actively involved in the study with us. So thank you. Okay, so taking a step back, where could VERVE-101 fit into the LDL cholesterol treatment landscape? We think ultimately a good landing point would be in patients who require LDL cholesterol lowering, deep LDL cholesterol lowering over decades. So if you think about the patients we enrolled, the average age was 54. Those patients are, you know, facing 20, 30 years of care. So single-course gene editing medicines may emerge as an option for those kind of patients to overcome the limitations of the chronic care model. Now, let me move to a couple of updates. Beyond the data, the U.S. FDA cleared our IND application for VERVE-101 in patients with HeFH. This allows us to initiate a trial in the U.S. The FDA reviewed our complete response, which included comprehensive experiments to address preclinical requests, but even more importantly, it included the Heart-1 clinical trial dataset that you just saw. We have planned to activate U.S. sites for VERVE-101 development, and this is the first IND for in vivo base editing. Our experience interacting with the agency over the last year generated a lot of learnings that are going to be valuable as we move forward with all of our future programs, VERVE-102, VERVE-201. In addition, we are thrilled to gain Eli Lilly as a collaborator for our PCSK9 and ANGPTL3 programs. As you likely know, Lilly purchased the rights to opt in for the PCSK9 and ANGPTL3 programs from Beam Therapeutics in a transaction with a total potential deal value of $600 million. Lilly's opt-in rights are characterized as follows: In exchange for paying for 33% of worldwide development costs and 50% of U.S. commercialization expenses, Lilly receives the right to 50% of U.S. profits. Ex- U.S. is retained by Verve. Verve retains control of development, and Verve books revenues. Lilly brings tremendous know-how in the cardiometabolic space. They bring resources, they bring expertise in late-stage drug development and commercialization for cardiovascular indications. We have a shared vision around application of gene editing to treat HeFH as well as ASCVD. Again, we couldn't be more excited about this development. As part of diligence, Verve provided to Lilly the Heart-1 clinical trial data as well as preclinical data for related CV programs. Now, let me walk you through the rest of the pipeline. We've talked a little bit about 101. I'm going to cover 102 in a minute. Both 101 and 102 target PCSK9, and they use the base editing technology. Our next target is ANGPTL3, VERVE-201. That will, that is a attempting to go after two indications, homozygous FH and refractory hypercholesterolemia, again, base editing technology. Then we have a program targeting Lp(a), and here, we'll not be using base editing technology, but rather a custom editor we're developing for this target. Custom editing technology we're developing for this target. And then we have a an undisclosed target, liver liver target, that's also atherosclerosis target, that currently is we're planning to use a base editor. And lastly, is an undisclosed target that's partnered with Vertex, and this is the only one of our programs that is not ASCVD based. This is really a straight-up liver disease that we're partnering with Vertex to work on. So VERVE-102. So VERVE-102 is an adenine-based editor, mRNA, and a guide RNA, exactly the same construct as VERVE-101, but packaged in a different delivery vehicle, a GalNAc-LNP, that's shown in the middle, and, designed again, the edit is designed to turn off the PCSK9 gene. So VERVE-101 is differentiated from VERVE-102 in a couple of ways. VERVE-102 has two components of the LNP that are different. One is the ionizable lipid. For VERVE-101, the ionizable lipid is licensed from Acuitas. For VERVE-102, the ionizable lipid is licensed from Novartis. In addition, 102 has a targeting ligand, GalNAc, that binds to a receptor on the surface of liver cells, ASGPR. So 102 can get into liver cells by any of two receptors, either the LDL receptor or ASGPR. Now, these differences may lead to improved potency for 102 compared to 101, and/or tissue specificity. Here's some data for 102 in non-human primates. On the x-axis is time, on the y-axis is LDL reduction in control animals, as well as VERVE-102, as well as VERVE-102 treated, and you can see there's a nice reduction in LDL that's durable here in this experiment out to six months. So we have very good data in non-human primates for both VERVE-101 and VERVE-102. Our plan is to simultaneously develop both, followed by the selection of one product candidate to take to Phase II. You can see on the timeline here that we are currently in the midst of Part A for 101, that's the dose escalation phase. We're going to transition to Part B, the dose expansion phase, in 2024. In parallel, we'll be conducting the Phase I for 102 in 2024, and then, based on the human data from both products, we'll select one of the two to take forward into a Phase II in 2025. Let me move to 201. 201 targets ANGPTL3, a compelling target with human genetics and pharmacology validation to lower LDL cholesterol via a mechanism that is additive to PCSK9. That's very important to emphasize. PC... So you have statins, and then you have PCSK9 inhibitors, lower LDL by about 50%-60% on top of statins. And then, ANGPTL3 mechanism will lower LDL by an additional 50% on top of PCSK9 and statin. You see the product on the left, VERVE-201, which is an mRNA for the base editor, a guide now that localizes to the ANGPTL3 gene, and here we're using our proprietary GalNAc-LNP delivery technology. In the middle, you see some preclinical data that we've shared publicly before. I'm summarizing here. We created a monkey model of a disease, homozygous familial hypercholesterolemia. We treated those monkeys with VERVE-201 and saw about a 45%-50% reduction in LDL cholesterol, and that's the data that's shown in the middle. We're anticipating clinical trial initiation for VERVE-201 in the second half of 2024. So what does 2024 and 2025 hold for Verve? Here are the anticipated milestones across the two programs for 2024 and 2025. Let's start with PCSK9. For VERVE-101, in 2024, we'll complete enrollment in the 2 high dose cohorts. So that's Part A, that's the dose escalation phase. That's the 0.45 and 0.6. We expect to go from the 10 patients we have right now to about 15 patients in Part A. And then Part B, we'll be expanding 1 dose into a larger number of individuals. That's the dose expansion phase. And then we'll pick a dose or two to take to Phase II based on that. For VERVE-102, we'll initiate a Phase I in the first half of 2024 and enroll that study. For VERVE-201, 2024, as I said, will hold a... We'll initiate the clinical trial in the second half of 2024. The anticipated milestone for 2025 are shown on the right. We'll have clinical data for both programs, 101 and 102. We will select one of the two to take to a randomized, placebo-controlled Phase II for the PCSK9 program. Okay, let me close with the next couple of thoughts. Come back to the beginning. You know, we're focused, we're well-positioned to realize our vision of developing one and done treatments for ASCVD. We have root human proof of concept.... We have several product candidates against highly validated ASCVD targets. We have an emerging regulatory path in the U.S. with the IND clearance. We have a new partner in Lilly, with a shared vision, the CV development expertise, as well as commercialization strength, and we're well capitalized with about $485 million in cash and a runway in 2026. So if you think about Verve, started in 2018 with the vision to develop single-course gene editing medicines. Five years later, we've gone from concept to proof of concept in humans for a first-in-class base editing treatment. And in the next five years, we are thrilled and excited to execute on our vision to get to single-course treatments for a range of indications. Thank you. Okay, we'll now move to the Q&A portion. I think we have a couple of folks that are gonna walk around with mics, and we're here to stay all night. Excellent. Say a lot. Whitney from Canaccord. First question, can you walk us through the dose extrapolation, I guess, from non-human primates to humans with 101? And just kind of how you arrived at the doses that you used. Part two of that question, I guess is: Do you have room to dose up if you decided you wanted to with 101? And then sorry, third part is how would you think about dosing 102 based on the non-human primate data you showed, I think, which looked about to be similar LDL lowering at 3 mg per kg, as we saw at 1.5 mg per kg in the non-human primates with 101. Yeah, that's a, that's a... Those are great questions. On the first question about the translation from monkey to human, we were thrilled with the translation here. You know, the monkey data predicted a safe starting dose and has predicted an efficacious dose and a range that really covered that full gamut. And so in this study, we do have the ability to go even higher, above 0.6, and that decision will be made based on what we see with the rest of the patients at 0.45, and the additional patients will dose at 0.6. Okay, and then I think, Whitney, what was your second question? Dosing of 102. Was it one- 102. Yeah. Yeah. I think you answered the first two together, but yeah, 102. 102, yes. So the 102, I think the starting dose for 102, we've not guided to that, but I think one thing to note is this LNP is different from the first LNP, the 101 LNP. This LNP uses an ionizable lipid that's licensed from Novartis. That's 102 uses the ionizable lipid license from Novartis. That is the same ionizable lipid that is being used in Intellia's products. And if you look at the Intellia's preclinical data in non-human primates, the two doses they studied in non-human primates that they've reported publicly are 3 mg/kg and 6 mg/kg. Correct. So, Whitney, I think that will give you a sense of how we might end up going in terms of the starting dose. Hi, Kostas here from BMO Capital Markets. Congrats on the data. A couple of questions from me. The first one is, based on the data we saw, do you think there is any impact on the therapy from the partially impaired LDL receptors that these patients have? Or you think this has no impact at all on the efficacy? And I have a couple of follow-ups. Well, you could see that we've gotten the efficacy band that we've been talking about for now, you know, a few years. This fits squarely into the target product profile that we set out to, accomplish. About a 40%-60% LDL lowering. And as you know, the current medicines that are out there, and this may be... There may be a bit of misunderstanding about what one should expect in terms of LDL lowering with maximal PCSK9 inhibition. So the antibodies pretty much reach maximal PCSK9 inhibition, and the antibodies in HeFH patients lower LDL in HeFH patients by about 50%-55%. It's a little higher in, non-HeFH patients, but so we're right there. You know, we have to dose more patients at 0.45 and 0.6. But we're seeing very good efficacy despite this 50% LDL-R deficiency. So I think, this LNP, as we've hypothesized, there's enough LDL receptor in these patients to be able to take it... You know, to be taken up and get the appropriate level of editing. Again, we have to dose more patients at these two dose levels, but what we're seeing so far fits within what our expectations were. Perfect. Thank you. And maybe one on the ALT elevation. Is there any way to characterize what grades those ALT elevations are? And do you think FDA will push back or other agencies will push back on these ALT elevations, cognizant that this is a one-time therapy, the ALT elevation is transient and may not be important, but any color around this ALT elevation and the extent of that would be helpful. Thank you. Yeah, we've characterized it here. It's a Grade 3 ALT elevation in the 0.6. Andrew, do you want to talk a bit about? Yeah. There's pretty standard adverse event scoring criteria for laboratory abnormalities like this, and we use those standard grading systems. So this adverse event was grade 3. It was transient. We don't think that this is gonna be dose limiting for a one-time therapy. Obviously, it'd be different if we're a chronic therapy. But at these levels of ALT elevation, it's transient, it's asymptomatic, there's no long-term injury to the liver. And there's some standard kind of ways of thinking about those liver risks, like looking at for elevations in bilirubin, such as Hy's law type findings that we did not see. Did not see. So, you know, we think this is a safety profile that would not preclude a broad administration profile. The FDA reviewed these data before allowing the U.S. study to go forward with the dose range that we've proposed here. Great, thank you. Maybe one follow-up here. Is there any way with modeling, given the dose response, to predict what dose would drive a higher grade of ALT elevation, for example, Grade 4, or it's not possible? Well, we've seen fairly consistent dose response for ALT elevation, and so far in 10 patients, it's a limited n. But, you know, I don't think that there's a... We-- I guess you probably could model, but I think we don't feel like we will be dose limited by ALT elevations, is probably the best way of putting it. Okay. Thank you so much. Congrats again. Thanks. Seamus Fernandez from Guggenheim. Just a few quick questions. One, a clarification on all the ALT questions. Just to keep it simple, did you provide all this data to FDA prior to them signing off on initiating the clinical program? Yes. Great. Did FDA require or ask for any protocol changes at all versus the data that you saw? No. Okay. Absolutely. So that, I think, simplifies a lot of that. Second question is, really just from an LDL and, kind of efficiency of editing perspective, can you just help us understand, you know, how, what you would view kind of looks like with the 0.45, we got sort of the evidence of maximal editing. With GalNAc, I think we saw an extraordinary kind of PK profile, from, actually Lilly's, Lp(a) RNAi. And, you know, that PK would imply very, very low risk of off-target editing, really just going right after the liver. So- Right. You know, in terms of GalNAc, what would kind of keep you on this 101 path, instead of, you know, kind of moving to the full GalNAc program with this and with your ANGPTL3? Yeah, I think for 101 versus 102, you know, as I said, we're excited by both. We have good data so far in humans for 101. We'll complete that, and then we'll have to see what 102 shows. We're super excited about 102 for the reasons you mentioned. The addition of GalNAc might give it more potency, might give it more specificity. I mean, one of the possibilities, Seamus, is that we get similar levels of efficacy between 101 and 102, but what if 102 is able to do it at 0.3 mg/kg? That would be a huge impact for the product going forward. So that's the kind of possibility that we might see, but, you know, we'll have to show in patients coming up. Oh, great. Luca Issi, RBC Capital Markets here. Maybe two quick ones, maybe Andrew, if I may. Can you just talk about the MI and why was it deemed potentially drug related? Was it just the chronological proximity to the infusion, or were there any other factors that led to that conclusion? For example, did that patient also experience material ALT elevation? Just trying to understand if this MI was actually inflammatory in nature or not, which is a question I think came up during the Q&A today. And then second, maybe going back to Kostas's questions, I know you're not slicing the data by genotype, but it looks like you had one patient that had LDL receptor that was intact. What was the knockdown in that patient versus the other patients at the same dose? Again, just trying to understand whether the LDL receptor here plays a role in the update. Yeah. Thank you so much. Yeah. So the determination of relatedness on the MI was based essentially entirely on the proximity to dosing. There was no substantial difference in any of the acute markers in that patient compared to any of the other patients in the higher dose cohorts. So there was nothing unique about that patient from their response. I think it truly does signify the more unstable cardiac physiology in that patient. With respect to your second question, I think, you know, it's obviously an understandable question. It's certainly, you know, heterozygous FH patients in general, as Sek alluded to, have had slightly less LDL lowering historically in lots of other trials. So it's, you know, reasonable to kinda ask that question. You know, it's a low end at this point, and we think it's probably not a good idea to try to overinterpret N of one type data in that context, so. It's just too early to do subgroup analysis, you know, when you have 10 patients and one person. So but I think this is something that we can test out as we enroll more patients. But I think there was a hypothesis going in by many that the LDLR deficiency would really impact any, you know, efficacy, and clearly, that's not the case. We're getting exactly the TPP that we're looking for, despite the fact that these patients have, most of them, almost all of them, had an LDLR mutation. Yeah, Myles Minter from Morgan Stanley. I think people are trying to reconcile in the 0.6 mg/kg- Yeah. Patient. Obviously, the PCSK9 knockdown and then the greatest LDL-C lowering that we saw there. My question is on, there's a lot of patients in this trial on concomitant statin therapies. Did you monitor compliance in that particular patient that become more compliant on statin therapy throughout? Because obviously, if you take statins, it's gonna elevate PCSK9, but also lower LDL-C. Yeah, that's a great question, and that's not an issue here. We've been very, very careful about communicating both to the physician and also the patient, that the background therapy stayed the same. Yeah. That's been monitored for, and there's no change in that patient in the background therapy. I think I wanna just address this kind of just data. I think that, you know, people have asked, "Okay, you're seeing this 47%, but the LDL effect is maybe a little more than... It's 55%. So what's going on there, you know?" And Andrew addressed this question, but we'll just bring this back during the Q&A earlier today. But the relationship between the degree of PCSK9 reduction and the degree of LDL reduction is a population relationship across hundreds of people or if not thousands of people. In any given person, that relationship actually can be quite a bit of a scatter variable. And this is data, our data from non-human primates. So each dot here represents a non-human primate. On the x-axis is the% change in PCSK9, on the y-axis is the% change in LDL. You can see aggregated, there is a strong pattern of correlation, lower PCSK9, lower LDL. But there are a lot of also individual data points that could actually be representative of this patient that we just in 0.6. So look at that data point at -40. That animal had a -40 in terms of PCSK9 reduction, but an 80% reduction in LDL. So this is just to make the point that in any given individual, there could be some variability, but when we get to larger numbers, we're gonna see this relationship, predictable relationship. This has been seen before with other PCSK9 therapies as well, that skew in the individual patient response levels. Just a quick follow-up. Did any patient on the 0.45 or the 0.6 mg per kg achieve normal levels of LDL-C, according to either ESC or ACC? Yeah, we haven't, you know, we haven't started to look at that, and this is really too early in terms of clinical development to have that as the goal. Yep. Because you saw the patients are at 190 when they started. So I think as we get to later stages, Phase II, Phase III, I think, the proportion of patients who reach, you know, on LDL goal would be a, would be a meaningful endpoint, but it's too early to kind of go there. We're really just trying to understand PD. Great. Dae Gon from Stifel. Thanks for the presentation and congrats on the data today. Couple, maybe I'll start with a clarification, just, going off of Seamus's earlier question on clarification. The MI, as well as the other CV SAEs, were they also presented to the FDA as part of their clinical hold resolution? And how do they feel about going into sort of the earlier slash less severe patients, having seen that data? Maybe I'll follow up after your answer. Yeah. I guess I'll just repeat myself. Every single piece of information that you saw today has been shown to the FDA and much more. Yes, the answer is yes. Thank you for the clarification. And then, Yeah. Let me just show you in terms of the... So this, this, this guidance from February, you know, so March last year, I think is very relevant, kind of where we have been, where we're going. So we should all just read this. "So subjects with severe or advanced disease may be more willing to accept the risks of an investigational human genome editing product. However, these subjects may be predisposed to experiencing more AEs or be receiving concomitant treatments, which could make the safety or effectiveness data difficult to interpret." So then this last sentence, I think, is your answer, which is: "Therefore, in some instances, subjects with less advanced or more moderate disease may be appropriate for inclusion in first-in-human clinical studies." And so this is the transition we're making, where we now have proof of concept, and we're gonna be able to move to patients with less advanced, more moderate disease. So perhaps this next question is irrelevant in that respect, but that second patient who did not provide that medical history, if you will, how do you, going forward, allow or enforce collection of the thorough data such that these types of patients might be somewhat excluded from inclusion going forward? And then one more follow-up after that. Fred, do you want to address that in terms of the- Yeah, it's a very good question, and we thought about it. I think, you know, again, I want to reiterate that it's these CV events, MI and other serious AV, CV events. ... are really not unexpected in this kind of population. So, but we are going to be adding as we expand to the moderate population, we'll be getting, you know, more, a broader population to avoid that. But we're also going to be adding procedures such as CT angiogram, especially in Phase I, before we have the chance to do a placebo comparison, to really look and understand the patients and really focus in on the ones that have a high lifetime risk, including the moderate risk, and trying to avoid any with acute, any acute risks as well. Great. Last question. There seems to be some confusion around the 0.6 mg per kg durability curve being farther out versus 0.45. If you could remind us sort of the trigger point, which one started first, and what was the ultimate decision point? Which data kind of led you to go down to 0.45? Was it PCSK9, LDL, safety, all of the above? Thanks so much. Let me show you that in a second. I may have broke it. I can get past it, yeah. Okay, very good. Andrew, do you want to cover this? Yeah. So, you're exactly right. The progression through the cohorts was 0.1 mg/kg, 3 patients, 0.3 mg/kg, 3 patients, and then we dosed the patient at 0.6. As you know, the study design was flexible, adaptive dose levels. And so when we saw this patient at 0.6 see a 55% reduction, that indicated that we had skipped over the dose response portion of the dose response curve. And so we wanted to electively enroll patients at 0.45, so we could see the dose response curve. That is, at the end of the day, the purpose of a Phase I study is not to hit, you know, 55% LDL lowering. It is to understand the dose response curve, and so that's why we did that. It is true that we saw the ALT elevation, and that indicated that we had, you know, we were, you know, crossing over into a different regimen to a degree, so we elected to enroll some patients at 0.45. We have every intention of going back to 0.6, as we've articulated, and we'll be doing that, you know, over the next few months. All right. Great. Rick Bienkowski from Cantor Fitzgerald. So since we have individual patient-level data here, I was wondering, do we know which two patients were in on statins, who were treated with the VERVE-101, and if you saw any differences in response, to, you know, PCSK9 knockdown in those patients? And my second question, I don't think we saw a time course of the PCSK9 knockdown, only the time average there. So I was wondering if you could qualitatively talk to the durability, of PCSK9 knockdown over time, and if it kind of matched what we saw with the LDL-C response. Yeah. So you know, again, the same caveat about subgroup analysis applies here, for with respect to two patients that were not on statin. It is also the case that those were two of the patients in earlier dose cohorts. So it's essentially impossible to kind of answer that question. With respect to PCSK9 durability, it largely was the same. So we've seen durability in the PCSK9 reductions. PCSK9, as you probably know, is a little bit more variable, so the error bars are a little bit bigger, but the exact same durability has been seen, particularly at 0.45 and 0.6. Thank you. Cory from LifeSci Capital. Touching upon the really unfortunate incident of a fatal cardiac arrest. You know, a lot of times in gene therapy studies, we sometimes can take these unfortunate events and gain some future benefit from it. Whether it's through looking at biodistribution or in this case, looking at potential for off-target edits or editing efficiency. Were you able to collect any samples from that patient for data down the line? And if so, are you planning on presenting that? No. Second one from us. Can you speak a little bit more to the potential mechanism of ALT elevations with lipid nanoparticles? Thinking about the switch from of ionizable lipids, is there a potential for an improved safety benefit moving from Acuitas to Novartis? Do you want to? Yeah. You know, I think the mechanism is of the ALT elevation is largely driven by the ionizable lipid itself, and that is largely essentially the amount of lipid that gets accumulated in the liver. So it is dose dependent and is ionizable lipid dependent. I can say that, you know, in our preclinical data, the Novartis lipid has less liver, less ALT elevations and presumably less liver, inflammation than the VERVE-101 Acuitas lipid. And I think, you know, there we do think that the Intellia experience with that lipid is, is likely relevant, where they have not seen significant ALT elevations in humans up to, you know, 1.25 mg per kg, roughly. So, I think, you know, that is another potential benefit of 102. Yeah. Hey, Andrea Tan, Goldman Sachs. Maybe a follow-up question there on the lipid that's being used in 102, which you've referenced Intellia using. Just given where they are right now in terms of performing studies to assess fertility risk, coming from the chemicals from that lipid, just curious if you're planning on any of these types of studies ahead of your own IND submission here, to maybe preempt the FDA's request. We have performed those studies ourselves. Yeah. I have a few questions from the webcast. The first few come from Eun Yang, from Jefferies. Two patients in the study had prior PCSK9 therapy. Why did they discontinue the prior treatment, and at what doses were they treated in the VERVE trial? I don't—we don't have that on the off the top of our head. But I think the reasons people discontinue PCSK9 therapy, you know, a range of different reasons in terms of cost or, you know, just a bunch of other- I think, as you know, about 50% of patients on the PCSK9 inhibitor will not be on it about 1-2 years later. So these patients would, you know, fall pretty typically into the pattern of past PCSK9 usage. The second question I have from Eun is, Verve, it's continuing to enroll patients in the 0.45 and 0.6 mg per kg cohorts to complete the dose escalation phase. How many more patients are you planning to enroll in those cohorts? We're planning to go to a total of 15, so we're right now at 10. So the 0.45 will go to 6 total, and the 0.6 will go to 3 total. And then I'm going to switch to, Eric Joseph from JP Morgan. His question is: How, if at all, are the patient entry criteria in the Heart-1 study being modified with cohort expansion? Fred? Was the question for the cohort expansion in the second cohort? How are the- Okay. criteria being modified? Yeah. The modification is to actually go to the more moderate patients. You know, we focused in on the heterozygous FH and severe advanced cardiovascular, you know, atherosclerotic disease. But now that we've got the information we have, we are able to open it up to more moderate patients. And we're also, as I mentioned earlier, doing the CT angiogram to continue to screen in Phase I. Dae Gon from Stifel again. Two questions on 102. Does this mean that once you do clear the CTA or IND in first half 2024, you would need to do the same thing, go for the severe as the first initial set of cohort of patients? That's, that's a no. Yeah. So, presumably similar as the expanded entry criteria that you're going to use. Right. When would you decide for your Part C, the 0.1 and 0.3 mg per kg dose patients, when would you decide on the final go-forward dose, and when would they be redosed with the, new now go-forward dose? The idea for Part C is to pick the dose that we take forward to dose expansion. So once we have that defined, that would potentially be the dose they get. In terms of the timing of the Part C, Andrew, do you want to? Yeah. There's a brief stagger, and then we initiate Part C Part B is initiated. Luca Issi, RBC Capital Markets. One big picture question here, maybe for our KOL. I think when we speak to some of your colleagues, there are clearly two camps. There's camp A, clearly enthusiastic about the promise of a one-and-done approach that can solve compliance. However, there's camp B, that knows there's lots of other drugs out there to lower cholesterol, and that maybe VERVE is overplaying a little bit the compliance issue. You're clearly camp A, but what do you think? What kind of data, if any, do you think camp B need to see in order to become camp A? Thanks so much. Yeah, I think that's a great question. I guess you're right, I am in camp A. But, you know, that's how physicians often are. Some are, you know, really enthusiastic about new approaches, others are skeptical. That's just human nature, and physicians are no different. I think the key, though, when we're talking about LDL control, is what real-life shows, and it shows that a good chunk of patients are off their generic statins. Why is that? You can't blame cost there. The drug's cheap. It's just for a variety of reasons that patients, even ones that have had heart attacks, just aren't... You know, 50% are off their statin in a year, as the registries repeatedly show. Dr. Bellinger already mentioned with the PCSK9 inhibitors, a similar sort of issue of patients coming off. You know, their costs might have a little bit to do with it, too, but certainly, it's just the idea of acknowledging that one is sick and getting repeated pills, repeated injections. So I do think, the idea of a one and done, really, will be appealing to patients and to physicians. As far as the ones that are skeptical, I think durability data is going to be what convinces them. So, you know, the data out to six months looks pretty durable to me, and if that continues with longer follow-up, that's the sort of data I think will make skeptics into believers. Hi again, this is Kostas from BMO Capital Markets. Maybe a couple of questions here, and more like general level. Base editing, I think we are forgetting a little bit about this is the first time that we see in vivo data from base editing. Any high level or even detailed lessons learned around base editing that we didn't know before? And maybe how would you compare it now to other approaches, CRISPR-Cas9 or potentially other approaches that are emerging? And then a follow-up irrelevant to the first one is, based on the timeline you presented, when exactly will Lilly be deciding whether or not to opt in for the programs that you can potentially partner? Thank you. In terms of the Lilly question, so they have the ability to opt in to 101 at the end of Phase I. They also have the ability to opt in at the end of—for 102 at the end of Phase I as well. So they're basically, you know, each product, they have the ability. Our sense is that they'll likely make that decision after seeing both 101 and 102 data. So that's likely when they'll decide. Yeah, that would be, that would be about right. And what your first question is? The basic. Oh, it works. In vivo. We didn't know that before. Yes. And so I think that's a huge step for that technology. You know, we're going after this disease. I think, you know, we're finding efficacy. I think there's a range of other diseases that could be approached now with base editing for liver, at least even. So I think, you know, it puts that technology in a good place. Thank you. And maybe one more. We saw that there are different approaches emerging in cardiovascular disease. One is epigenetic editing, and we recently saw some data here at the conference. Any comments around epigenetic editing and maybe pros and cons around that versus base editing? Thank you. Yeah, no, I don't wanna go too far into these other technologies. I think everybody's trying to develop, you know, specific areas of benefit that they might have over others. I think we feel very comfortable with, you know, the unmet need here, why we're doing this. There is a huge unmet need. You know, despite all that's available, this number here, right, 3% of goal, I mean, that's a fact, you know? So I think... And we have an approach, a one and done, that I think could solve this or help solve, at least provide another option for this. But this is just one technology, base editing. Others may come in and say, "All right, I have this other technology for one and done as well," and I think that's great. Ultimately, if they can get it to work, it'll be great for patients to have multiple options. Thank you. Other comments or questions? Good. Anything else from the webcast? Okay. All right, wonderful. Thank you so much for joining us on this very special day, and look forward to staying connected. Thank you.