Luca, senior biotech analyst here at RBC Capital Markets. Today is a great privilege to have Verve as part of our 2025 Global Healthcare Conference. Representing the company, we have Sek Kathiresan, who is the Chief Executive Officer here. Sek, thanks so much for joining us. We look forward to the conversation. How are you doing today? I'm doing terrific. Thank you so much for having us, Luca. Yeah, absolutely. Absolutely. We have a long list of questions here, but maybe let's start big picture. Maybe if you can walk us through some of the progress that the organization has made recently, and maybe most importantly, what's ahead here for Verve? Yeah, so as you know, Verve is developing one-time therapies that have the profile of lifelong cholesterol reduction. One-time IV infusion, lifelong LDL reduction. Our lead program targets a gene PCSK9. We just disclosed phase one data, initial phase one data for this product, and the emerging profile is very exciting. Basically, we were able to give a two to four-hour infusion to patients with heterozygous FH or premature coronary artery disease. It was well tolerated, excellent safety, both laboratory and clinical safety. We had very good efficacy in terms of pharmacodynamics with LDL reductions in the range of 50%-60%, mean of 59%. Actually, we had one person who got up to 69%. Really nice efficacy. For the mechanism, for the base editing mechanism that we're using, we actually also disclosed data in terms of two-year durability. The idea of a one-time infusion, and then two years later, the patient's LDL cholesterol was still down about 60%. A really exciting profile. I think we're going to be able to get to our vision of a one-dose future to treat chronic disease. That's really the lead program. We have a second program, same concept, but a different target, ANGPTL3, and then a third program that's in the clinic now. And then a third program in Lp(a) targeting that gene. In terms of what's ahead for this year, for the PCSK9 program, you can expect the full dose escalation data in the second half of the year. We have a really nice partnership with Eli Lilly. We're expecting an opt-in decision from them in the second half of the year. The last item for this year is going to be dosing of the first patient in the phase two. For the second program, the ANGPTL3 program, we expect to give a program update in the second half of the year, and that could be a data update depending on enrollment. Got it. Got it. Got it. Super helpful. Great overview. Let's talk about FDA a little bit. Obviously, lots of changes with obviously Dr. Prasad now being the head of CBER. You know, he's been pretty outspoken about some of the recent approval, including Sarepta for gene therapy, the use of surrogate biomarker in MRD for it's kind of a little bit more like kind of his bread and butter in oncology, but also he has made some comment also on gene editing for PCSK9. I would say probably most investors would argue that under him, the regulatory bar is probably higher than it was before with Dr. Peter Marks. Would you have a different view on how you're thinking about implications for Verve? Yeah, no, I think there's been a lot of discussion about the new leadership. We're actually excited to engage with him. I think it may surprise you to hear me say that I think we're actually quite aligned with the kind of things that Dr. Prasad has advocated for. Number one, he's advocated for surrogate endpoints that track closely with clinical disease, not newfangled biomarkers that may or may not correlate with clinical outcomes. It turns out in that realm, LDL, there's no better biomarker in the world than LDL in terms of prediction of coronary events, tracking with correlation with coronary disease events, clinical coronary disease events. That is a great place to be aligned. This is a very well-accepted surrogate endpoint for cardiovascular disease. The other area that he's spoken about is products that deliver meaningful value rather than marginal value. Specifically, he said that drugs that get approved based on accelerated approval and then stay on the market without the confirmatory studies, often delivering marginal value, are challenging to accept in the marketplace. It turns out, you know, the profile that I just described for Verve 102 targeting PCSK9, that's going to be anything but marginal value. It has the potential to decrease LDL after a single infusion 60% to 70% and do it for the rest of your life. That's estimated to reduce risk of coronary disease based on human genetics by 80% to 90%. This is the leading cause of death in the world. Having an agent that can really transform the way we care for this disease, I think, is going to add a lot of value, not marginal value. Got it. Got it. That's actually very helpful. Can you maybe talk about your transition from your first gen to your second gen, if you will? Obviously, the first gen had some safety setbacks. Just maybe walk us through what is different about this construct and why you're confident that you're going to be able to spare some of the toxicity that you've seen for your first gen, even if you are going to a slightly higher dose going forward. Walk us through that part. Yeah, so our product concept in terms of getting to this kind of one-dose future is an editor. For in our case, it's an adenine base editor and then a guide RNA. Those two RNA molecules are delivered in a lipid nanoparticle delivery system. We had two product candidates when we started with the PCSK9 program. The first product candidate called VERVE-101 and the second one called VERVE-102. The data I described a few minutes ago was for VERVE-102, the latest, the next-gen molecule. The first molecule, VERVE-101, had a different lipid nanoparticle delivery system than VERVE-102. That's the principal difference between the two. They actually have the same editor, the same guide. Okay? How are the lipid nanoparticle delivery systems different? VERVE-101 had a certain chemical component called an ionizable lipid and a PEG lipid, whereas VERVE-102 has a different ionizable lipid, different PEG lipid, and has a targeting ligand added to it, a carbohydrate, a GalNAc. These two differences, these sets of differences in the delivery system really, I think, will account for the safety differences that we're seeing. For VERVE-101, as you said, we had transient laboratory abnormalities after the acute infusion, and those were reversible, but nevertheless led us to pause that first study last year. We transitioned to VERVE- 102 in April of last year, and then over the last year have been dose escalating and now see both in non-clinical studies as well as our clinical data that VERVE-102 is much better tolerated than VERVE-101. Got it. Got it. What’s your expectations for the high dose that you’re going to show us? You’re like both on the safety side as well as maybe on the incremental efficacy you’re hoping to see from the high dose. Yeah, that's a good question. The data we released on April 14th had three dose levels, 0.3 mg, 0.45 mg, 0.6 mg per kg. At the highest dose levels where we saw the efficacy numbers that I mentioned and the safety look great across the dose levels, we've escalated now to the next dose level, 0.7 mg per kg. The reason we're doing that is it looks like we may still have efficacy on the left on the table. Could we have everybody not just getting over 50% LDL lowering, but maybe everybody getting over 55% or 60% even? It looks like that could be possible. Of course, we have to see what the safety is at the next dose level. Now, we've already dosed a few patients at 0.7 mg, and thankfully the safety looks identical to the earlier dose levels, and then the pharmacodynamics is pending. We really are hopeful that at the next dose level, we'll kind of pick up that efficacy that might be on the table, but also keep the safety that we've already seen. Gotcha. That's super helpful. You mentioned the Eli Lilly opt-in decision later this year, maybe two-part question. One, can you remind us the mechanics of that Eli Lilly and the economics behind that opt-in? Two, can you consider renegotiating that deal a little bit so that maybe they pick up a little bit higher proportion of the cost, especially in this environment for maybe a higher proportion of the either U.S. rights or ex-U.S. rights? Like how should we think about that part? Yeah, so remember the legacy of this deal is really we had had a relationship with Beam Therapeutics. In exchange for exclusive access to the base editor for PCSK9 and ANGPTL3, we gave Beam minority product rights. Beam basically Lilly purchased those rights from Beam about two years ago because they were interested in what we were doing. Lilly now holds those rights. They have the ability to opt into the program in the second half of the year. We expect that in the second half of the year. That opt-in, they'll evaluate our clinical data, our preclinical data, budget we give them as well as the clinical development plan. Once they make the decision to opt in, they have some certain obligations and rights. The obligations are that they have to pay for a third of worldwide development costs and 50% of U.S. commercialization expenses. The rights they have are 50% of U.S. profits. The other 50% U.S. is Verve, 100% ex-U.S. is us. Really, majority rights held by us, economic rights held by us, minority by Lilly. Again, their obligations are a third of worldwide development expenses and 50% of U.S. commercialization. We're excited to have them as a partner. They truly are best set, I think, in this vision of a multi-modality pipeline for targets of high interest. Targets of high interest for them in cardiovascular disease include Lp(a) and ANGPTL3, where for both of those products, they have an siRNA already, both of those targets. They also are very interested in PCSK9. They'd like to have a pipeline of pill, maybe an si, as well as a one-time gene editing option for each of these targets. We're excited about the partnership. You ask a very good question as to whether we can renegotiate to have them pick up more of the tab. That is certainly possible, and we'll consider that. Got it. Got it. Very, very, very clear. Maybe one last one on PCSK9 before we pivot to ANGPTL3. What are your thoughts on the orals? I think the oral small molecules are making progress there. I mean, Merck is obviously very committed to run a very, very large cardiovascular outcome trial, 17,000 patients, if I recall it correctly. AstraZeneca obviously has a molecule too, and we can debate food effect and whatnot, but clearly you have two large pharma companies very committed to this class and developing an oral. Is that potentially going to raise the bar further for you in the sense that obviously the convenience of an oral is difficult to beat or you kind of see yourself in a little bit of a different category? Those are more orthogonal/complementary mechanisms of action versus what you're trying to do. Any thoughts there? Yeah, a couple of comments. It just speaks to, I think, how important PCSK9 is as a target, first of all. You have Amgen, you have Sanofi, Regeneron, you have Novartis, and now you have two more, AZ and Merck. Basically every major pharma has a stake in this target. I think that's great for the field. A second is that, you know, what's the unmet need that we're trying to address? Because we get asked this all the time. There's lots of options to lower cholesterol, different pills, three pills already on the market, three injectables. What are you trying to accomplish with your new approach? The basic fact is, despite what's available already, the majority of patients are not at treatment goal for LDL cholesterol. In fact, roughly one in two patients who get started on any cardiovascular medication have discontinued it at one year after initiation. This is for a set of therapies that are supposed to be taken for decades. At one year, half the people are not on their cholesterol medication. How are they getting their cholesterol lowered? They're not. That's unlikely to change with a fourth pill or a fifth pill that comes on the market. That's the unmet need we're trying to address. The idea of a one-time therapy, lifelong cholesterol reduction. There's a huge amount of white space really left, I think, for something like our approach to come and address the unmet need. We've also looked, and we've shared this with you before, to understand patient demand here. In a future treatment landscape where there is a daily pill for PCSK9, where there are twice-a-month injections, twice-a-year injection, and one-and-done option, what would patient preferences be? What might physician preferences be among in this future treatment landscape? Both, so on the patient side, about a 1/3 of patients would prefer a one-time therapy. For physicians, for HCFH patients, for about 40% of the HCFH patients, physicians, cardiologists would prefer a one-time therapy rather than a daily pill or those other options. I think there is a fair amount of demand to solve this unmet need of true efficacy. Efficacy is really the unmet need right now. Sure. Yeah. That's actually very helpful. Let's maybe pivot to ANGPTL3. Maybe just you already alluded to it, but maybe just remind us why you're excited about this target. When we look back at some of the setback that we've seen from Ionis and Pfizer, they obviously had to discontinue that molecule. Walk us through why you think that that safety signal was actually off target and not on target. Yeah. So ANGPTL3 inactivating this target basically lowers two things, blood LDL cholesterol and blood triglycerides. There's very compelling human genetic evidence for this target. Basically, there are people walking around who have the gene completely turned off. They have very low lipid levels. They're protected from heart disease. There's also pharmacologic validation from Regeneron's Evkeeza, where a monoclonal antibody that neutralizes blood ANGPTL3 lowers blood LDL and blood triglycerides. And that's an FDA-approved drug. It's a very, very good target for a few different indications. We're excited about it because it is a mechanism of LDL lowering that is additive to PCSK9 inactivation. It can actually build off of our existing first product and add to it. It has a range of indications, both LDL-based and triglyceride-based. That's the reason for the excitement. In terms of kind of what might be prior molecules, there was an ASO that was being developed by Ionis and Pfizer that stopped at phase two because of some liver fat increase. That seems now pretty clear to be ASO-related. It was a dose-dependent increase. The reason I can say that is that human genetic evidence, so the people that I mentioned earlier that are completely deficient in ANGPTL3, they do not have increases in liver fat. There have been two different siRNAs that have been developed, one by Lilly and one by Arrowhead. A different modality against ANGPTL3. They've been taken all the way to phase two. There have been liver MRIs performed in those patients over time. There's not an increase in liver fat. In fact, in the Eli Lilly study just reported at the American College of Cardiology, there's actually a decrease in liver fat with treatment. I think it's pretty clear that the earlier signal was really due to the molecule rather than the target. Makes sense. Makes sense. Yeah. Maybe one of your competitors, CRISPR, actually showed some data recently. It was just a press release. We still have to see either a publication or a presentation in a medical meeting. What was your take on that dataset and how you're thinking about how you could potentially differentiate versus what they have shown so far? Yeah. So for VERVE-201, sorry, our molecule for targeting ANGPTL3, VERVE-201, that's in the clinic right now. We're in the dose escalation by the end of the year. As I said earlier, we hope to have a program update. It could be a data update depending on enrollment. We're excited about the progress there. Now, the really nice thing about that product is it uses the same GalNAc- LNP delivery system that we're using with the PCSK9 product that's now been de-risked in terms of liver and liver safety. It uses the same base editor, and then the guide RNA is just different. A lot of the components have already been de-risked. In terms of the data from CRISPR, yeah, it was initial data. I think just one patient for each of the two different phenotypes, LDL and triglycerides. It showed that the target is they're seeing what you should see, which is LDL comes down, triglyceride comes down. What we don't know yet is what is the true dose response because we didn't see that yet in terms of full dataset and at what dose are you going to get safety and efficacy. Gotcha. Gotcha. That's helpful. You already alluded to it, but love to double-click. How are you thinking about a study design here for your ANGPTL3 molecule? Can you maybe leverage any of the learnings from your PCSK9's approach and maybe start a little bit higher doses versus the dose that you started with your PCSK9? Just walk us through the study design and maybe what you're hoping to show us later this year. Yeah. The study design is very similar to the data we just presented for the Heart-2 trial of VERVE-102. The study for ANGPTL3, the VERVE-201, is called PulseOne. That study is a single ascending dose design, a few patients in each of several dose levels. As I said, we're in the dose escalation now. We were able to start at a higher dose, leveraging the learnings from VERVE-102 targeting PCSK9. I think by the end of the year or early next year, what we hope to show is a dataset similar to what we just showed on April 14th for VERVE-102 targeting PCSK9. That's, of course, several dose levels, safety, tolerability, and then PD. The PD here would be degree of reduction in blood ANGPTL3 from baseline, degree of LDL reduction, degree of triglyceride reduction. Got it. Got it. Super helpful. Maybe in the last few minutes, let's talk about Lp(a). Maybe a big picture before we ask you about your molecule. I think everybody's waiting for this Novartis's data. Obviously, this remains an hypothesis as of today, that lowering Lp(a) actually drives the cardiovascular benefit for patients. Obviously, Novartis has pushed out the readout to next year. It was supposed to be this year. What was your read on that news? Are you still confident that that trial will actually hit the primary endpoint? Yeah. I think that trial, the Horizon trial of an ASO targeting Lp(a) from Novartis and Ionis is an event-driven trial. So they're so blinded. I think the simplest explanation would be that the event rate estimation was a little bit off. It is challenging to estimate event rates in the context of kind of maximal LDL lowering, which is what they got in their patient population. That was kind of a requirement coming into the study. They're looking to see the benefit of Lp(a) lowering when LDL is maximally suppressed. In that situation, it might be challenging to actually estimate the baseline event rates. If you're off a little bit, you can imagine if it's an event-driven trial, it could take a little longer. I think that's what's going on. I do think that the trial will be positive. From the human genetic data, it's very clear that Lp(a) is a causal molecule. There are four important questions that still remain to be answered regarding Lp(a) and relationship to cardiovascular events. It's how much Lp(a) lowering do you need for how long in which patients to get what degree of MACE reduction. Those four questions are still unanswered. They'll only be answered probably when you look at the totality of the three trials that are being planned or being conducted and that'll all read out over the next few years. The first of those is Horizon. The second of those is an OCEAN trial, siRNA from Amgen and Arrowhead. The third is the Eli Lilly Lp(a) siRNA. Sure. Especially because all of these trials have different inclusion criteria. This trial has different primary endpoints, right? Including stroke, not including stroke. They have a different lens. Now Eli Lilly is even launching a trial with primary prevention, right? We will see what happens with that trial. That is actually very helpful. Can you just maybe walk us through your molecule? Maybe your Lp(a)? What are you doing there with Lilly? Yeah. We're partnered with Lilly. This is a different structure than the ANGPTL3 and PCSK9, where they have this opt-in option. This one is much more of a standard big pharma biotech collaboration, where we're doing all the research to develop a gene editing solution to Lp(a). They're paying for it. At the end of phase one, the product transfers over to them, and we get royalties and milestones. The product we're developing uses a GalNAc- LNP delivery system that is common to VERVE-102 and VERVE-201. It targets and activates Lp(a). It's a novel editor. It's not a base editor. The first two programs use base editing. This one uses a new editing technology that we've developed internally. It's in preclinical right now and hope to get to the clinical stage soon. Got it. Got it. That's actually very helpful. I think in this first-gen versus second-gen for PCSK9, I mean, obviously, one of the key differences here was having GalNAc that helps liver tropism and obviously spares some of the toxicity you've seen from the first-gen. How are you thinking about potentially monetizing that technology? How are you thinking about potential BD opportunities? Walk us through how you're hoping to maximize the value of that piece of innovation that you guys have developed internally. Yeah. So we're very proud. It's a proprietary GalNAc. It's been added to the LNP. I think we're the first to kind of get a GalNAc- LNP into patients to show that it can work. I think you saw the safety profile looks really good. There were no dose-dependent elevations in ALT. There is a lot of interest in delivery to the liver, even to the liver. We've gotten approached by several firms. We're working our way through thinking about letting people access that. Yeah, so stay tuned. Got it. Got it. Very helpful. Maybe the last one here. CRISPR earlier this week announced a deal, earlier stage deal, but still potentially signaling that that company's thinking beyond gene editing because obviously they have licensed assets from China that is an siRNA. Again, open-ended question. What was your reaction to that news? What were your thoughts? I think I saw an interview with Sam Kulkarni, the CEO, explaining their rationale. I think they had a couple of different reasons that they said that they're going into now, siRNA, in addition to CRISPR-Cas9-based gene editing. One is the target. They feel like some targets you don't want to permanently inactivate. In this case, it's a coagulation target where permanent inactivation could lead to bleeding. You would want that to be reversible, and maybe it's not with the gene editing. That's one reason. The second reason is I think they're interested in building a multi-modality pipeline, a cardiovascular franchise. SiRNA kind of allows for that. I think the third reason is they felt like they wanted to get to commercial opportunity quicker. They feel like siRNA could allow them to do that. I think these are strategic choices that they're making. That's my understanding of why they made that choice. Got it. Got it. Super helpful. I have a lot more questions, but no more time. Sek, thanks again for joining us. Thanks, everyone, for joining today. We'll talk soon. Thanks again. Appreciate it. Awesome. Yeah. No, absolutely. Always a pleasure. Maybe we're surprised, but CRISPR. We're a little bit surprised.