It's been valuable because I went—why I think I told you I went to Penn for—I went to Yemen, I went to Columbia for grad school, which is like, yeah. Very, very good. It's been valuable. Yeah. I know. I know. Yeah. I mean, we'll talk later. Great. Thanks, everyone, for joining us. I'm Andrea Newkirk, one of the biotech analysts at Goldman Sachs, and I'm really pleased to be joined by Sek Kathiresan, CEO of Verve. Thanks so much, Sek. Our pleasure. Thank you so much. Maybe we'll just jump right into it. Just a couple of months ago, you announced the HEART-2 data. Maybe walk us through that. What were you so excited about? Because this does come on the back of HEART-1 a couple of years ago, where there had been a little bit of a setback. Maybe just walk us through HEART-2. Yeah. Maybe before I do that, Andrea, just take a step back and say, what are we trying to accomplish, and how did this data set really move the ball forward? Verve is focused on gene editing for cardiovascular disease, and the concept is one-time therapy, lifelong lowering of cholesterol, as a way to treat coronary heart disease or atherosclerotic cardiovascular disease. People often ask us, well, there are lots of options already to lower blood cholesterol. Why do we need a new approach? The unmet need here really has to do with what we term enduring efficacy. The idea is that with current approaches, basically most individuals, maybe 50%, up to 50%, after initiating a cholesterol-lowering therapy, within one year are no longer on them. They are not getting cholesterol lowering for decades like they are supposed to. What we started with in 2018 was this concept of a one-time therapy, lifelong cholesterol lowering. Really get enduring efficacy for patients. What that will lead to, if you're able to get LDL lowered by a good amount for a long time, is dramatic reduction in coronary heart disease risk. That was the idea. Over the last few years, we've been able to get this product concept to work in cells, mice, non-human primates. We had a first version that we took to patients. That was the HEART-1 trial for VERVE-101. We'll come back to that in a minute. We had another version, VERVE-102, a next-gen compound in the HEART-2 trial that we started last April. The data for that compound is what we disclosed on April 14. We disclosed data for the first 14 patients across three dose levels. We were able to show that we can get LDL lowering up to 69% with a mean of 59% in the highest dose level. Everybody in that high dose group got over 50% lowering. It was incredibly well tolerated. The acute infusion really had no major issues in terms of infusion reactions. Only one out of the 14 patients had an infusion-related reaction. On the laboratory side, it had a very good profile in terms of no elevation in ALT or platelets, no change in platelets, and no clinical events. It was a really good safety profile, very encouraging efficacy. We had durability from that earlier product that we also disclosed. This gene editing product, durability we saw out to two years after the one-time infusion. About a 60% lowering of LDL. Then two years later, the LDL was still down 60%. Really all kind of pointing to our original vision of a one-time therapy, a one-dose future for the treatment of atherosclerotic cardiovascular disease could really become a reality. This is why we're so excited. It's really the vision we set out with looks like it's going to be possible. Maybe before we dig into the most recent data set, just to remind us the difference between VERVE-101 and VERVE-102, and what gives you the confidence that that durability signal that you saw in that first-gen asset will translate to now your second-gen? Yeah. 101 and 102 have the same cargo. They basically have the same base editor, same guide RNA. That is really the guts of an editing system. That is really what gives you the efficacy and durability because that is what makes the change, in our case, in the liver and the PCSK9 gene sequence. What is different between the two is the delivery system. The RNA molecules, the mRNA for the editor and the guide RNA, are packaged in a little fat bubble called the lipid nanoparticle. 101 has a certain composition. 102 has a different composition. The reason we switched it out between 101 and 102 is that we knew that there was some risk with the delivery, particularly around laboratory safety when we infused. There could be a risk. We wanted to really have two different options available to de-risk that. What we've learned, both from preclinical studies and our now human experience, is that 102, with its different lipid nanoparticle composition, has basically a wider therapeutic index. We're not seeing any of the laboratory abnormalities we saw with 101. That's really the key difference. In addition to the composition difference, another component that's different is we added a targeting ligand called GalNAc to VERVE- 102 that binds to a receptor that's specific to liver cells, only on liver cells, called ASGPR. That is another wrinkle and innovation, really, proprietary innovation that we added to 102. We're very excited about 102 because it retains the cargo from 101, but it has this entirely different lipid nanoparticle delivery system. When you think about this delivery system, I think we've talked in the past that there's some components of it that parallel what Intellia is using. Obviously, Intellia has been in the news recently with some updates in their program. Just maybe to level set for everyone, is there any risk to VERVE-102 based off of the liver elevations that they've seen? Yeah. Intellia reported, I think, a couple of weeks ago now, a grade 4 ALT elevation in their phase III program. We do not believe there's read-through to us. Let me walk you through why. There are basically two types of patterns of LFT elevation after infusion of the lipid nanoparticle. Remember our drug, all these in vivo liver gene editing medicines are basically given through a peripheral intravenous dripped in over two to four hours. When you infuse, then there's a pattern that's early elevation in ALT. By early, I mean typically within the first week. Everybody agrees that's basically due to the lipid nanoparticle. That lipid nanoparticle can affect liver cells, and you have a transient rise and then fall. We saw that with 101. We didn't see it with 102. We saw with 101. Beam has seen it with their LNP. Intellia has seen it. That's not the pattern that was described by Intellia a couple of weeks ago. Rather, the Intellia pattern was late. The peak was actually at day 28. That is not LNP-related, at least according to Intellia. That is why we do not feel there is read-through to us. The question is, what is it, this late rise? There are a number of hypotheses out there, and I do not want to speculate. Suffice to say, we do not think it is LNP-related. Even though we share the same ionizable lipid as Intellia in VERVE-102, we do not believe there will be read-through. Got it. Perfect. That's helpful. Maybe we can go back to the HEART-2 data here. As you think about VERVE-102 and that TPP that you defined before you saw the data, now you've seen some of the data emerge from the first 14 patients, yet you're still dosing higher. Maybe help us understand what you're thinking you'd like to see potentially at this fourth dose. What would be the ideal TPP here? Yeah. So our TPP is basically LDL reduction above 50% for patients with ASCVD, above 40% for patients with HeFH, basically matching Inclisiran, the siRNA that has a very similar mechanism of action in terms of reducing protein production from the liver. So that's our TPP. And then, of course, we're differentiated in the fact that we have lifelong LDL reduction, ideally, and they are a few months. That's the key difference. At least the degree of reduction, we want to match them. Now, what we saw at the highest dose level, this is like between 50-60 mg of total RNA administered. We had three patients in that group. We saw a mean of 59%, a max of 69%, and every single participant had above 50%. This was a mix of both HeFH patients and ASCVD. We're very encouraged. You're asking, all right, then if that's the case, why are you going to a next dose level? The reason is we think there still may be efficacy left on the table. You saw in our dose—well, I should describe the fact that we were able to show individual-level data. On the x-axis is the milligrams of RNA received. On the y-axis is the percentage LDL reduction. It was a straight line down right now. It's a linear relationship across 14 participants. The more RNA you got, the greater the LDL reduction. At some point, that straight line down will transition to a plateau from a linear to a sigmoidal relationship. We need to understand when that is. This is our only chance to do it in the dose escalation. That's why we're escalating. Got it. You have touched on it a little, or you have referenced it a little, the dosing paradigm here, fixed dose versus the weight-based, weight-based being what you studied here. You did have an analysis of fixed dose and the effect there. Maybe just taking a step back, what is the rationale behind evaluating it or maybe parsing out the data in this way? How does that inform your dosing strategy or how you are thinking about next steps? Yeah. This is a really important point for the field. The field of in vivo gene editing is shifting to fixed doses in milligrams of total RNA delivered rather than weight-based. We're making that shift. You'll see that Intellia has fixed doses of 55 mg for their TTR product. Beam is basically evaluating fixed doses of 30 mg, 60 mg and 75 mg for their alpha-1 antitrypsin product. We started with milligram per kilogram. We also presented analyses in terms of milligrams of RNA, the fixed doses. The reason the shift is happening is this kind of product is unique in the sense that when you infuse into the bloodstream, almost all of it goes right to the liver right away. It's not going to the rest of the body. Milligram per kilogram is useful when there's widespread body distribution. Here, you're essentially just treating the liver. The principle is that, let's say, you're two times heavier than your neighbor, your liver is actually not two times heavier. That is why the mg per kg is not particularly helpful for this kind of product, whereas the fixed dose can be. What you saw was this beautiful linear relationship between the fixed dose we've given to patients and the degree of LDL reduction, which is the registration endpoint. We are going to move likely to fixed doses when we transition from phase I to phase II later in the year. We are guiding to a first patient dose by the end of the year in the phase II. The phase II will likely involve two fixed doses, roughly 30 patients in each of two fixed doses. Got it. And then just really quickly, in terms of we've talked about LDL, your TPP in terms of LDL reduction, how does it look as you think about PCSK9 reduction? And does that matter? How strong is the correlation between LDL and PCSK9? I think we've talked in the past as we looked at the HEART-1 data that PCSK9, those correlations are on a population level. But just remind us there. Yeah. I think what we're very great situation is that we have two biomarkers of PD, LDL cholesterol and PCSK9. And one of them, the LDL cholesterol, is actually the FDA registration endpoint. It is a very unusual situation, right? What we're seeing is really very clear relationship between the degree of RNA administered and the LDL reduction. That's probably what's going to guide us in terms of dose selection. We also see a very nice relationship, a dose-dependent relationship with PCSK9. Given ultimately the clinically relevant endpoint is LDL, that's what's going to guide dose selection. Yeah. Got it. And then just maybe really quickly here, as of your last earnings call, you have mentioned dosing two patients at the fourth dose. Just any additional updates you can share on that front? Only that we'll be presenting, we plan to present the full dose escalation in the second half of the year at a major medical meeting. Got it. Maybe speak a little bit more about what the expectations are for that additional or maybe for that fulsome data set that comes, how many patients in total we've seen 14. What is the end going to look like? Yeah. We haven't guided to that in terms of specifics. Certainly, we want to, again, we want to see that transition from linear to sigmoidal. One of the items that I think you can expect is the durability because that's something we didn't really get into with this data set on April 14th. By the second half of the year, we should have a good amount of durability info across the various dose levels. If you remember, our first patient dose in 2022 with VERVE-102 was April of last year. If you're going into the second half of the year this year, you're going to have some patients more than 12 months of follow-up data and then a bunch of patients in the three to six-month range. We have right now talked mostly about durability from 101 because that's now up to two years plus. For the second half data disclosure, we'll be able to give a bit more fulsome info on durability for 102. As you asked earlier, we expect to fully carry through because it's the same editor, the same guide. Maybe speaking about durability or as you think about this and you've gone out, you've done your market research, what is the extent of durability that people are looking for to really get comfortable that this is truly a one-time product? Yeah. Maybe we can talk a little bit about the biology here because this, I think, surprises people, right? Also, people have ideas around viral vector gene therapy, giving something back. There have been challenges there with durability. Why is gene editing going to be different? First of all, this is different. What we're trying to do is change your own DNA in the liver, right, endogenous DNA. We're not trying to give something foreign, but rather the change is within the DNA sequence within your own liver cell. The liver does regenerate in humans and in non-human primates. If there's regeneration, that typically happens every six to nine months, all the liver cells turnover. How could there be durability? The reason is that when we come in and do the editing initially in the liver cells, we're editing the cells that are responsible for the turnover so that when they divide to give forth new cells, they're carrying forward the edit that we already made. That is why there's durability. You can see with the two-year data that we showed for 101, that's well beyond the standard regeneration time of six to nine months. It really gives you a sense, yes, there's editing happening in the cells that are responsible for regeneration. Now, in non-human primates, there's data now for almost eight years of durability for in vivo gene editing, again, really supporting this concept. This is going to be permanent. In humans, Intellia has data for four years for TTR, for in vivo gene editing. We have data, as you said, as we showed, for two years. We think this is going to be fundamentally different than viral vector gene therapy. Two other points are that if there are issues with waning durability over time, we do not think there will be. One thing about LNPs, again, in contrast to viruses, is they can be redosed. You can kind of give another, not that I do not think we will need that, but it can be done. What do clinicians and payers and so forth think? One example to think about is some of the groups in the U.S., for example, ICER. When they model for cost-effectiveness, they will give you credit for a really long time durability if they see within about two years that it is flat. Okay? After that, they'll assume they'll give you credit for five or even more. I think that's a pretty good time point to think about, at least for external bodies as to what they're looking for. Interesting. The other side of the, so durability of efficacy, but many are also looking for what is the long-term safety profile. Do you believe that that same two-year implies five years translates over to the safety side? If you have a clean profile at two years, can you assume that that's going to be the case moving forward? Yeah. I think for any of these kind of therapies, it's always about risk-benefit, right? What you're balancing here is the actual risk that these patients are going to die of a heart attack in the next one to five years, which is an incredibly real risk for these patients, right? Because atherosclerosis in these high-risk patients remains a leading cause of death in the world. You're balancing that real risk of fatal heart attack versus a really, really low theoretical risk of an off-target edit in some portion of the genome leading in a single cell to a cancer event. That's what people worry about in terms of long-term safety. Once you get through the acute safety issue of infusion, then you're like, "Okay, editing is done. The drug is out of the body. You're left with these edits. You're left with lower cholesterol. Is there something untoward that's going to happen over time? We think that the way we've de-risked by showing that there's basically no detectable off-targets really minimizes that low probability that was there to start with. You have to balance that theoretical risk versus the real risk of a person, again, having a serious cardiac issue. That's kind of how I think about it. I think that's the way patients will think about it and physicians will think about it because we've talked about this. There are plenty of procedures that patients go through every day that are irreversible, that are intended to be permanent. Any surgery you can think of has risks, short-term, long-term risks. Why do patients go through it? Because they think the benefit is going to exceed the risk. It's going to be the same approach here. This is less of a drug, I would say, more of like a molecular surgery intended to have lifelong benefit. I think that when we get to registration in a few years, we'll have four or five years of follow-up in some of these patients that were dosed last year, right? All the patients in phase I and phase II, once you get our drug, you're in the long-term follow-up for 15 years. That's mandated by basically regulators around the world. They're going to have long-term follow-up in terms of these safety issues. We'll have that kind of data in probably hundreds of patients in a few years. That will be the starting point for people's assessment of risk versus benefit. Maybe as you think about the regulatory environment that we're in, because this has been a topic that has increasingly been top of mind here, the regulatory flexibility, what the agency may or may not be willing to allow here. Have you detected any changes in the nature of your conversations that you're seeing or that you're having right now? Do you think, how do you think gene editing as a modality is being viewed at the agency right now? I think there was a fair amount of uncertainty a couple of months ago with the departure of Peter Marks, the announcement of Dr. Vinay Prasad. I think in the last, I don't know, four or five weeks, there's been a lot of information coming out of FDA that they're actually very supportive of this technology. You saw there was a meeting last week on Thursday. It included the Head of HHS, the Head of the NIH, the Head of FDA, Marty Makary, and the Head of CBER, Dr. Prasad. What were they all crowing about? It was actually in vivo-based editing. It was this example from the University of Pennsylvania, actually, I'm proud to say my first postdoctoral fellow, Kiran Musunuru, basically having done this N of 1 for a baby that was really sick, developing a custom in vivo base editor to correct the gene defect. And the baby just, I think, left the hospital last week. I think there's a lot of openness to this approach. Now, the question we get asked is, "Okay, well, it's a rare disease. Is the same kind of applied to what we're trying to do?" I actually think that, and I think they've actually talked about this. The language is the administration wants treatments that address the root cause of disease, the root cause of chronic disease, right? What's the root cause of the largest chronic disease in the world, atherosclerosis? It's LDL. The idea that we're going to be able to give a single therapy one time and address this root cause rather than asking somebody to take a pill daily for 30 years or injections twice a month for 30 years, I think gets at this value proposition that they're looking for. I'm actually quite optimistic that this administration sees how this approach can transform how we care for patients. Maybe that's a good segue to the work that you've been doing to understand that point, how physicians, how patients might look at a one-time therapy that's novel. Maybe talk to us about the work that you've been doing there and what you've been finding out. Yeah. I think we've surveyed cardiologists in the U.S. We've surveyed actually, it's a third-party survey of patients who have high cholesterol or have established heart disease. Both of those give very consistent results, which is there's a remarkable openness among patients and physicians for this kind of approach. The early adopters, I think, are going to be patients, younger patients probably, who've either suffered a heart attack at a young age because they're facing 30-40 years of care, LDL care with injections or pills, daily pills, or patients who have inherited the high cholesterol from their parents. It's not their lifestyle or diet, but rather they have a genetic condition called heterozygous familial hypercholesterolemia. Both of those groups are pretty sizable. It's about 3 million patients with HeFH. Of the 25 million people in the U.S. and Europe with atherosclerotic cardiovascular disease, about 20% of them, it has happened at a young age, men less than 55, women less than 65. These are sizable groups of people who look like they are going to be even more open than the average person. In terms of the actual statistics, we presented to patients a future treatment landscape for cholesterol lowering of a daily pill, twice-a-month injection, twice-a-year injection, or a one-time gene editing approach. About a third of people preferred the one-time gene editing. When you do the same thing for cardiologists, for HeFH patients, for about 40% of their HeFH patients, cardiologists preferred a one-time gene edit compared to those other options. For ASCVD patients, and this is a huge group, for about 20% of them, they preferred a one-time therapy compared to the other options. There is a lot of openness. Maybe the last point is, okay, that's patients, that's physicians. What about payers? There is still work to be done. I think there are some fundamentals in terms of our product that I think will allow us a fair amount of flexibility on pricing and market access. The reason is our product is very different from what people think about in terms of gene editing, gene therapy. Most people associate a million-dollar price tag with any of those, with these kind of products. That is not going to be us because of a couple of things. One is we have lots of patients, so we do not have to resort to our rare disease pricing. Second is the cost of manufacturing here can be very manageable. This kind of product, about 100 micrograms, can be made for about $3. We know that because of the COVID experience. The COVID vaccines are basically mRNA packaged in a lipid nanoparticle. We are RNA packaged in a lipid nanoparticle. We're not going to be giving 100 micrograms, but rather like 60 mg or 50 mg. Let's say $1,500 a dose. At that price point in terms of cost of manufacturing, whatever price we set, there's going to be a lot of flexibility, I think, in terms of margin. We are going to be very different from anything else out there. This is, I think, part of the excitement why I think we can fundamentally change the conversation on pricing and market access for these kind of medicines with something like VERVE-102 How do oral PCSK9 play into this picture? Obviously, you saw this morning with Merck having their positive data readout here. How does that change the calculation or that split of the proportion of patients, do you think? The future treatment landscape that we propose to cardiologists included oral PCSK9. Even with that, for 40% of their HeFH patients, cardiologists prefer a one-time therapy. That's because, again, we're trying to really, again, fundamentally change from a chronic care model for chronic disease to a one-dose future. What does the oral PCSK9 do? It just adds to the chronic care armamentarium. We already have lots of options in the chronic care armamentarium. We have three pills right now that can be taken daily to lower cholesterol. We have two injections and another injection coming on the way. Despite the availability of all those chronic care options, very few patients actually are at LDL goal. Less than, I think, 5% of eligible ASCVD patients are actually on a PCSK9. We do not think that is going to change that much with the availability of an oral additional fourth or fifth pill. Got it. So yeah. Maybe one last question here as it relates to your PCSK9. Later this year, you will also deliver the opt-in package to your partner, Lilly. Maybe walk us through the expectations or maybe the extent of data or not data, but disclosure that you might provide to the street as this gets underway. Yeah. One of the things we're guiding to this year is the decision from Eli Lilly on the opt-in. Just to walk through that, they have the ability to opt in to this product in the second half of the year. What the mechanics are is that we will put together the dose escalation data. We'll put together a development budget as well as a clinical development plan and preclinical data that we've already generated. Put all that together, give that to them. They'll review that data and then make a decision. Once they opt- in, they would be responsible for a third of worldwide development costs. In return, they would get 50% of U.S. profits. They'd also be responsible for 50% of U.S. commercialization expenses. The 50% of U.S. profits is theirs. The other 50% is us. The 100% of ex-U.S. is us. That's the relationship. We're excited. They were very pleased to see the product profile that emerged from the April 14th disclosure. We're excited to partner with them for the second half of the year. Maybe as it relates to Lilly's approach in cardiovascular, obviously, they have other assets going after different targets. You do as well. Maybe in the last two and a half minutes that we have here, talk us through the three pillars that you have. So we talked PCSK9. That's largely our discussion here. But ANGPTL3, LPA, how do you see the relative? Yeah. Our company was constructed around the three main carriers of cholesterol, basically LDL, triglyceride-rich lipoproteins, and lipoprotein(a). We have a target that goes after each of those, PCSK9 for LDL, ANGPTL3 for LDL and triglyceride-rich lipoproteins, lipoprotein(a), LPA gene for lipoprotein(a). We talked about our first product. We're very excited about the second and third because they're going to leverage the delivery system that we have, the GalNAc LNP. The second product, ANGPTL3, it's in the clinic now. We'll hopefully have data for that in the second half of this year. Right now, got into a program update, but that could be a data update based on enrollment. That product is really nicely de-risked because it has the same GalNAc LNP, the same base editor. All that's switched out is the guide. That is an exciting development. LPA, we're partnered with Lilly on that, but a slightly different structure than the PCSK9 relationship. Here, this is much more typical of a standard big pharma biotech where we're doing all the research now. They're paying for all of it. At the end of phase one, the program transfers over to them, and we get royalties and milestones. Now, their approach to cardiovascular disease, I think we're nicely aligned where we see in the future these very compelling targets like PCSK9, like LPA. For any given target, there basically is a multi-modality pipeline. There could be a pill. There could be a twice-a-month injection, twice-a-year injection, and a one-time option. All of those can coexist in the marketplace because these indications are very large. You see that strategy playing out for Lilly, for example, for LPA. They have a daily pill that's in finished phase II. They have an siRNA that's in a phase III right now. They're working with us for gene editing. This is, I think, the future of cardiovascular care. We seem to, both companies seem to have a nice alignment on what are those high-priority targets: PCSK9, ANGPTL3, LPA. For example, they have an siRNA against ANGPTL3 that's in phase II called Zerlasiran. Again, that's, I think, why the relationship between the two companies has been so strong. Awesome. Maybe in the final closing seconds here, just remind us where things stand in terms of your cash runway. If Lilly does opt-in, how does that impact it? Yeah. So we closed the first quarter with about $500 million in cash. This takes us to middle of 2027. It gets us the phase I data for 102, the phase I data for 201, the ANGPTL3 product, as well as getting into the phase II and maybe even completing the phase II for 102. Really a lot of milestones. This runway to mid 2027 does not include Lilly opt-in. It is conservative in that sense. Once Lilly opts in, it can extend our runway probably by another quarter or two. Got it. Perfect. With that, Sek, thank you so much. Thanks, everyone, for joining us.