Good afternoon, everyone. My name is Gena Wang. I'm a SMID Cap Biotech Analyst at Barclays. It is my great pleasure to introduce our next presenting company, Verve Therapeutics. With me, we have Sekar Kathiresan, Chief Executive Officer and a Co-Founder. Maybe before we dive into the questions, could you give us a very high-level overview of Verve? Yeah, thank you very much, Gena, and thanks to the Barclays team for the opportunity to be here. The problem we're trying to solve, Gena, is heart attack, the leading cause of death in the world. Heart attack is caused by cholesterol building up in the heart arteries over time. What we're trying to do is develop a medicine, a one-time treatment that would actually lead to lifelong cholesterol lowering. Our approach is gene editing, in vivo gene editing. The idea is a single intravenous infusion that will lead to a cholesterol-raising gene being turned off in the liver and then lead to cholesterol lowering for a lifetime. That's the concept we started the company with in 2018. Over the last seven years, we have made really nice progress to get this new approach to work in cells and animal models. Now we're testing in patients. I think the big exciting news for the company is really that we'll have data for our lead product, VERVE-102, in Q2 of this year. This is a phase I first-in-human study in a couple of patient populations, heterozygous FH, as well as premature coronary artery disease patients. Okay. Maybe I will take one step back. When the company started, you have maybe a lot of capability to do the gene editing. Maybe why choose base editing? Yeah, so we started the company with this idea of a one-time therapy, lifelong cholesterol lowering. We actually had the targets that we wanted to go after already in hand based on maybe a decade or so of human genetics research. These targets were PCSK9, ANGPTL3, and LPA. These genes have tremendous human genetic validation. They really were the focal point for the company. The question really became, how do we actually turn these genes off in the liver? What technology do we use? We specifically set up the company to be technology flexible, both on the editing side and also on delivery to the liver. We got access to a couple of different gene editing technologies, one called standard CRISPR-Cas9, which cuts DNA, and the second called base editing, which was kind of new on the scene in 2017, 2018 when we were starting the company. We tested both, was really a bake-off between the two, in model systems for a couple of years, in the first couple of years of the company, before prioritizing base editing. Base editing was chosen because it is inherently a bit safer because it avoids the DNA cuts that could potentially lead to translocations of DNA. What base editing does is it's really a single spelling change is made in the DNA. One letter is swapped out for another. That's the mechanism we're using to turn off, for example, the PCSK9 gene with the VERVE- 102 product. Okay, very helpful. I think another part of very important is the lipid nanoparticle, the delivery vehicle. I think there seems a lot of confusion regarding lipid nanoparticle between Verve and Beam and first- gen, second- gen. Maybe give us a little bit of background regarding the first- gen lipid nanoparticle and second- gen lipid nanoparticle. Even yesterday, data update being there, there was some read-through regarding the lipid nanoparticle. If you can lay out regarding the lipid nanoparticle, the history of a lipid nanoparticle. The drug product that we're working with is the editing system. And that's two pieces of RNA, an mRNA for the editor, a guide RNA that tells the editor where to go in the genome to make the spelling change. Those two pieces of RNA need to be delivered to the liver. We're delivering it through the bloodstream. In order to get these two pieces of RNA to the liver, they need to be packaged in something. The packaging here is a little fat bubble that's basically the lipid nanoparticle. These lipid nanoparticles have several components that go into them. One of them is called an ionizable lipid, which is probably the key chemical component of the lipid nanoparticles. When we started the company, we were figuring out which editor to use, but we were also flexible on what delivery option. We evaluated a range of lipid nanoparticles. We ended up settling on two different delivery systems to pursue near simultaneously in the preclinical work and then into the clinic. That is why we have two products, VERVE- 101 and VERVE- 102. They both have the same inner contents, the same guide RNA and the same mRNA, but they differ in the composition of the lipid nanoparticle. We tested VERVE- 101 first in patients. We actually were able to provide strong human proof of concept for in vivo base editing. We basically got it to work. We were able to lower cholesterol by 50%-60%. We were able to do it durably, meaning that in a patient, the LDL came down 55%. Eighteen months later, after the one-time intravenous infusion, the LDL was still down 55%. That is 101 in terms of efficacy and durability. We had a challenge with the lipid nanoparticle. The lipid nanoparticle led to transient rises in liver function tests, as well as in one patient, a drop in the platelet count. Therefore, we paused the 101 study last year. We transitioned to 102. 102, again, is the same cargo that we already showed worked, but has a different lipid nanoparticle. What we are looking to show in Q2 is that this new product, VERVE- 102, the next-gen product, will retain the LDL reduction that we saw, as well as the durability that we saw with 101, but avoid the transient laboratory abnormalities. That is really what we are hoping to show in Q2. Now, every lipid nanoparticle is its own beast. There is no such thing as just an LNP. We have a certain LNP in 101. We have a different one in 102. Beam has yet a different one. They did put out some data on Monday, but it is really with a different delivery system than what we are using. Has the 102 lipid nanoparticle has anything similar or different compared to, say, whether Beam or Intellia, the lipid nanoparticle that also has shown quite safe and in lots of patients already, any similarity or difference there? That's a great question. 102, the current version being tested in patients, the ionizable lipid that's part of 102, it's the same ionizable lipid that Intellia is using in all of its programs in its two programs in the clinic. That ionizable lipid has been tested now in a couple of hundred patients and has, as you mentioned, a good safety profile. That gives us confidence that 102 is going to have the same kind of profile. In addition, we have preclinical data that supports that 102 will avoid those laboratory abnormalities. Of course, we've dosed patients now across three dose levels in the phase one with VERVE- 102. Again, we're going to show that data coming up and hope to show that it'll avoid the laboratory abnormalities. The 101 versus 102 lipid nanoparticle was never the same as Beam lipid nanoparticle? I'm actually not sure what ionizable lipid Beam is using. Okay. Okay. Regarding your first-gen lipid nanoparticle that had a safety issue, did you see that safety issue in the non-human primates data or the animal data? We saw in non-human primates the transient rise in liver function tests, yes. We also saw in some animals a drop in platelets, but at doses higher than the no-observed adverse event limit. Okay. What makes you confident it's not because of PCSK9 target, given that's also LDL receptor mutation, right? Yeah. We are very confident that the laboratory changes are not due to the cargo or the editing of the PCSK9 gene. The reason we can say that is because we've done experiments where we actually deliver a lipid nanoparticle with an inactive guide in the middle so that it's not capable of editing. You are just testing the lipid nanoparticle component itself. When you do that, you actually see the transient rise in ALT as well, really suggesting that it's not the cargo or the editing apparatus, but rather the actual lipid nanoparticle itself that's leading to these changes. I see. Have you tested the first-gen lipid nanoparticles in healthy volunteers or in not the disease model? Did you also see similar safety issues? We did test the VERVE- 101 in a phase I study in 13 patients. That's where we saw the abnormalities, yeah. Right. My question is, could that be because of PCSK9? Oh, I see. You are saying that you are not going after PCSK9. My question is, could that be the patient population itself? No. I think it's really inherent to the ionizable lipid. That's really what it looks like, yeah. Okay, good. The best proof of that is going to be the data we're going to show in Q2, where we are testing essentially the PCSK9 editor wrapped in a different lipid nanoparticle. What we hope to show is that, again, the editing is there. The LDL comes down. It's durable, but there are no laboratory abnormalities. There's a good safety profile because we've switched out the lipid nanoparticle. Maybe comments on your second-gen lipid nanoparticle because you do add a GalNAc there, right? You're adding additional uptake mechanisms for the lipid nanoparticle. Maybe if you can highlight that. The lipid nanoparticle that we're using now, again, one of the components, the ionizable lipid, is different. Then there's a second difference between 101 and 102. That is we've added a targeting ligand to 102, a GalNAc carbohydrate. It's a proprietary GalNAc that we developed internally. We have a U.S. patent for it. This GalNAc allows the lipid nanoparticle to get into liver cells through the receptor for GalNAc, which is ASGPR. It can get in through a port of entry that is independent of the typical mechanism, which is LDL receptor. Okay. You did mention the first- gen, you did see in non-human primates the sign of just safety toxicity profile. What kind of safety profile do you see in the non-human primates and how much higher dose did you use in the non-human primates? For 102? 102, yeah. Yeah. For 102, we actually have a tolerability profile and a safety profile that's quite distinct from 101 in non-human primates. Again, really giving us confidence in terms of the human data that we're going to show coming up, that basically it's going to be much better tolerated without any of the ALT or platelet changes that we saw with 101. What was the highest dose you tested in the non-human primates? I don't think we have provided public guidance on that. Okay. Okay. Now regarding your Heart-2 data update, you will have three cohorts, 0.3, 0.45, 0.6 mg per kg. Maybe for the 2Q data, first is, do you see these data real-time? Yes. It's an open-label trial. We're seeing the data in real time. Okay. You should see all those safety and all the measurement you are collecting now, right? That's right. Okay. Do you think, given you just comment on the same cargo, do you expect similar level of, say, LDL and the PCSK9 knocking down or reduction level with this dose range? Yeah. Just to set expectations for the data release, we're guiding to three dose levels, 0.3 mg per kg, 0.45 mg per kg, 0.6 mg per kg. We're guiding to a minimum of 10-12 patients across those three dose levels. Each patient will have at least 28 days of follow-up. It'll be safety. Endpoints will be safety, the blood LDL level, and blood PCSK9 level. The reason we chose the 28-day endpoint is that by 28 days, there's a nadir that's reached for both the LDL and the PCSK9. That's really the data set. In terms of benchmarks of LDL reduction and PCSK9 reduction, we come back to our therapeutic product profile that we're hoping to accomplish. Our TPP is really going to be inclisiran-like. Inclisiran is an siRNA targeting PCSK9 that's on the market now. What degree of LDL reduction does that product achieve in patients? It depends on the type of patient. In patients with HeFH, heterozygous familial hypercholesterolemia, a severe genetic disease that we're targeting initially with this product, inclisiran lowers LDL by about 40%. In atherosclerotic cardiovascular disease patients, inclisiran lowers LDL by about 50%. Forty and 50 are the LDL benchmarks for HeFH and ASCVD. There are PCSK9 reduction benchmarks as well. Those are 60% reduction for HeFH and 70% reduction for ASCVD. That is really what we're hoping to show and accomplish with this trial. Recall, or you should know, that we have two types of patients in this trial. One is HeFH, and the other is ASCVD patients who've basically suffered ASCVD at a young age, men less than 55, women less than 65 who might have suffered a heart attack. These are the two patient populations being studied in the Heart-2 trial. The first three cohorts, you're hoping you can reach what you just said, the benchmark. Regarding the safety, usually how soon, if there is a safety issue, how soon you will see the safety issue happen? Yeah. The laboratory abnormalities that people usually see with lipid nanoparticle infusion are all acute. Within the first couple of days, within the first week for sure, are when you might see any of these safety issues. So far, I don't know if you can comment on how many patients already enrolled, but so far you haven't seen any safety issue. We characterized safety in the 10-K just a couple of weeks ago. As of the mid-February data cutoff date, there were no treatment-related serious adverse events and no clinically significant laboratory abnormalities. The profile looked quite reassuring. What's the purpose of the fourth dose? Is that because you want to test better efficacy or you were thinking wanted to see how high you can go for drug to be still safe? I think there are two reasons. This is the dose escalation. This is the only chance we'll really be able to explore the full dose range. For a new product, typically you do the dose escalation to understand not only where you're getting maximal therapeutic effect, but also the safety margin from that point. Those are the safety margin you might have from that point on. Those are the two reasons to kind of continue on to a fourth dose level. What kind of, because I see like three, 0.45, 0.6, is it fair to think like a fourth dose would be 0.75? We haven't provided public guidance on that fourth dose level just yet, yeah. Okay. When we see others, including Beam and Intellia, Intellia started with weight-based and then translated to fixed dose, and I think Beam is using fixed dose. Are you also planning to use fixed dose in the future? Yes. Okay. Any specific dose you do not want to go beyond? I think the dose range that, for example, Intellia explored, 0.1 mg per kg to 1 mg per kg, is roughly the range I think that our constraints are as well because we are, again, using the same ionizable lipid, which is a primary driver of efficacy and safety for LNPs. I see. With additional GalNAc, do you think it will help with drug delivery or safety? The main help we expect, the main reason we developed the GalNAc is it should equalize any potential efficacy differences between patients who are wild type versus mutations in the LDL receptor. The most common mutation leading to heterozygous FH, so very high cholesterol in the blood early in life and premature heart attacks, this genetic disease, are mutations in the LDL receptor. If you recall, I said that the main way that the LNP gets into the hepatocytes is through the LDL receptor. You can imagine that in this patient population, a standard lipid nanoparticle might have trouble getting in. The idea behind the GalNAc is to essentially allow for LNP to get in through a receptor other than LDL receptors. It should equalize any potential efficacy differences. Okay. Good. Maybe I think a very common pushback, and I cover tons of gene editing companies and lots of investor pushback, is if a disease is well served, nobody will use a gene editing drug. Maybe what is your counterargument? Yeah. I think that's probably the biggest misconception about our company and what we're trying to do in the sense that this disease is not well served by current cholesterol-lowering medications because people equate efficacy with a certain degree of cholesterol reduction at one time point. For example, a 50% reduction at day 28. True efficacy here is not only how low at a single time point, but for how long. It is really area under the curve over time. That is where all of the current approaches fall short. They actually leave efficacy on the table because the average patient who gets started on a cholesterol-lowering medication, 50% of them are no longer on them at just one year. That means from year two to year 50, when you're supposed to be on it for a long time, they're getting zero LDL reduction. That is the unmet need that we're trying to serve. It is pretty clear that if you could lower LDL, let's say 40-50 milligram per deciliter for 30-40 years, you would actually probably wipe out this disease. You would not have coronary heart disease. That is really the fundamental promise of what we're trying to do, really change the way this disease is cared for and have a transformative impact because we're addressing true efficacy. Okay. Good. Maybe more the partnership question. I think Vertex ended their collaboration regarding a serious liver disease. Maybe any more color you can share on your end, why they terminate, and what is your plan for that asset? Yeah. That asset, we started a collaboration with them a couple of years ago. They funded this whole effort. We developed a bespoke editor for this asset. Now it's wholly owned. We are planning to progress it independently right now. The reason they moved on from this asset is for portfolio prioritization reasons, and that's Vertex's rationale. It gives us an opportunity to progress this product ourselves and make a decision in the near term as to whether we're going to continue it ourselves or attempt to partner again. Our most important collaboration is really with Eli Lilly for our first two programs, the PCSK9 program as well as the second asset, the ANGPTL3 asset. Lilly has the ability to opt in at the end of phase one and step in and basically share in development costs, pay for a third of worldwide development costs. In return, they would get 50% of U.S. profits. We get the other 50%. We have 100% ex-U.S., and we control development book revenues. We are really excited about them as a potential partner as we develop this product forward later this year. For the mid-year update, when you, I think second quarter, right? When you update data, will you also have some feedback from Lilly or you will share the data first, then you go to Lilly? Yeah. So there are three major milestones this year for our lead asset. One is the initial data release across the three cohorts in Q2. Then second, in the second half of the year, we should have the full dose escalation data release. The third event this year is really the Lilly opt-in. It is really three distinct events separated in time. First, the Q2 data release for three cohorts. Second, the full dose escalation in the second half. Third is the Lilly opt-in decision. Okay. Good. I know we are running over time, but this is a very productive discussion. Thank you very much, and we look forward to the data update later this year. Thank you, Gena. Thank you.