All right, well, thanks, everybody. I guess we reached our final fireside chat for the day. I'm Seamus Fernandez, one of the biopharma analysts here at Guggenheim. This is our inaugural innovations conference, and in the realm of innovation, I think Verve Therapeutics really you know sort of stands as breaking quite a lot of new ground in therapeutics. So really thrilled to have Sekar Kathiresan here with us. He's the CEO of Verve. Sek, so maybe just to remind everyone what Verve is trying to do and why, not only is it ambitious, it's necessary. Yeah, thanks, Seamus. Really a pleasure to be here. So Verve is developing a one-time therapy that could potentially lead to lifelong lowering of blood cholesterol, and the insight that kind of started the company is really that if one's cholesterol is really low lifelong, it's very hard to get a heart attack. That insight comes from human genetics, where we and others identified a series of genes where mutations turned off the gene led to lifelong low cholesterol, and people were remarkably protected against heart attack. So we developed this idea in 2018 that, hey, what if we could develop a medicine that would actually turn off a given cholesterol-raising gene in the liver, do it permanently, and lead to lifelong lowering of cholesterol and protection against heart attack. So that's what, that's how Verve started. This is 2018. Now, six years later, what we've done is able to show that that concept can work in cells, mice, non-human primates, and then took it to patients. This year, we now have three different products that we've taken to the clinic, all with the same idea: in vivo, gene editing, base editing, one-time therapy leading to lowering of cholesterol. Our first program targets PCSK9, and we have two products that target PCSK9: VERVE- 101 and VERVE- 102. And 102 is really now in the clinic, and we'll have data for in the second half, first half of next year, and we can talk more about that. 201 targets ANGPTL3, and we just dosed our first patient for that program. We can talk more about that. And then we have a program targeting lipoprotein(a) as well. And we've chosen these three targets for in our pipeline because there are three distinct axes of risk on the lipid side: LDL, triglyceride-rich lipoproteins, and lipoprotein(a). And our idea was that let's have a product against each one of these three axes, and that should really address the unmet need in cardiovascular disease. And maybe one item to kind of add on here is that we often get asked, do you really need to gene edit for cholesterol? You know, why not just take a statin or other medications that are available, alternatives that are available? And I think the unmet need here is that these medicines that are available currently require really lifelong therapy. And the bottom line is that's not happening. About half the patients who get started on a cardiovascular medication basically are no longer on them within six months of initiation. That's for a range of reasons. Sometimes it's adherence, sometimes it's cost, sometimes it's access, sometimes it's people don't like to be reminded that they're sick and they, you know, take a pill every day. And so what we're looking to do is really address that unmet need and offer patients a one-time therapy, and lifelong cholesterol lowering. Great. You know, you mentioned data coming in 2025. In terms of just the data events in 2025, but also some key partner decisions that could be coming in 2025, what are you most excited about? What are you most focused on? Yeah, we're very focused on our lead asset, our lead program, PCSK9. As I said, that program has two products. The pro product that is going to be data rich in 2025 is VERVE-102. This is a base editor guide RNA targeting PCSK9 package in a proprietary GalNAc lipid nanoparticle. We just announced that we've dosed the first two cohorts, 0.3 mg/kg and 0.45 mg/kg, and we expect to have the initial data in the first half of next year. So next year for this product is shaping up to be initial data release in the first half of next year, and then in the second half of next year, probably a final data release, as well as a decision from Eli Lilly regarding opt-in into this program. Yeah. So, you know, you've kind of narrowed the timing of Heart-2 to the first half of 2025. Maybe just in terms of the update itself, what should we anticipate? And I think the company has decided to place 101 on hold until you sort of capture that data. What are you really looking for in that data in terms of the expectations, and what's key in that sort of compare-contrast? Yeah, so maybe take a step back and say, what have we learned so far in terms of this mission of a one-time therapy, lifelong cholesterol lowering? The first thing we've learned is, like, the whole thing can work, and we didn't know that a few years ago, and we know that based on 101, the first product, the editor and guide RNA work as designed. And we know that because in the patients treated, we just released updated durability data, and we've been able to see LDL lowering, you know, 50%-60%. And then in the patient that's been followed the longest, with an efficacious dose, that patient had durability out to 18 months. This is actually a 29-year-old individual who had a heart attack two years earlier at age 27, came into our trial, got our medicine 101, and LDL came down 57% at one month, and then 18 months later, the LDL is still down 57%, really suggesting that the guide RNA and the editor work as designed, entirely new technology that we worked with starting in 2018. Now, but we had some safety challenges with the acute infusion of the lipid nanoparticle, and that was we had a transient rise in liver function tests. We had one patient drop in platelets, and all reversible, all no clinical consequence but nevertheless, we paused that first program to better understand why we might be having these these laboratory abnormalities, and second, we had this second product in line, and really wanted to to see how that would perform. We've done an investigation to understand why VERVE-101 led to those laboratory abnormalities, and these, this lab non-clinical studies, confirm our hypothesis that it was really the lipid nanoparticle, not the editor, not the guide, but rather the lipid nanoparticle delivery system that was responsible for the laboratory safety abnormalities. And our second product, VERVE-102, retains the editor and the guide from the first product, so the stuff that worked. And, but it's a different delivery system. It's a GalNAc lipid nanoparticle delivery system. And this switch of the delivery system, we think, will, help us avoid the laboratory safety abnormalities. So we think 102 will retain the efficacy and durability we saw with 101, but again, avoid the laboratory safety abnormalities. And so we started dosing VERVE-102, in late April, early May, and, have now, as I said, announced a seven-patient dose across two dose levels. And then in the first half of next year, we should be able to release data. Now the volume of data, how many patients, where we're going to do it, that's where we're getting all the questions. We'll be able to give more details on each of those items, probably in the new year. Great. So maybe let's go through the decision points on just GalNAc in general. It just seems like the efficiency would be better. So there was definitely some variability in the 101 data set. How would you know, the efficiency of the GalNAc, you know, potentially improve the consistency of the results? Yeah, so, there, just to kind of again, take a step back, between 101 and 102, as I said, the cargo is the same, the guide and the editor. What's different is the lipid nanoparticle delivery system, and there are three differences between 101 and 102. First is the ionizable lipid, one of the key lipid components, is different. The second is the PEG lipid is different. And then the third is we've added this GalNAc targeting ligand to 102, and 101 did not have that. The key determinant of potency and efficacy, and safety, actually, is the bulk component, which is the ionizable lipid. The ionizable lipid in 101 was obtained; we licensed it from a company called Acuitas. The ionizable lipid in 102, we licensed from Novartis. The ionizable lipid being used in 102 has been used by another company in third-party clinical trials that and it's well tolerated. So we have and our own preclinical studies for 102 suggest that there's actually a wider safety window for 102. So all of that gives us confidence, and the seven patients we've dosed gives us confidence in the 102 lipid. In terms of the GalNAc addition, it is really designed to equalize any efficacy issues that may be there between patients who lack the LDL receptor versus those who are fully competent in the LDL receptor, because the LDL receptor is the mechanism, is the means by which lipid nanoparticles enter hepatocytes. In our patient population, that have the very high cholesterol that we're starting with, called heterozygous familial hypercholesterolemia, a genetic disease that leads to sky-high cholesterol from birth, these patients have a defect in the LDL receptor, and therefore standard lipid nanoparticles may have challenges getting in. So the GalNAc addition, what it does is allows the lipid nanoparticle to get into hepatocytes, to liver cells, through a receptor other than LDL receptor, namely the GalNAc receptor called ASGPR. So we do think that the addition of the GalNAc should help reduce the variability that we saw in the first program. Great. And in terms of the decision point for Lilly and sort of the timeline for an opt-in, can you just help us understand, you know, the data hits, you announce the data, when, and what's the timeline for the Lilly's opt-in decision potentially? Yeah, so our first two programs, the PCSK9 program and the ANGPTL3 program, Eli Lilly has the ability to opt in to these programs after phase 1. They purchased rights that had been held by Beam Therapeutics. They purchased these rights from Beam last year. And these rights can be characterized as follows. If they opt in, they basically pay for a third of worldwide development costs from that point onward. And in return, they get 50% of U.S. profits and 100% of ex-US is us. The other 50% of U.S. is us and 100% of ex-US is us. So those are the rights. We control development, Verve controls development, and Verve books revenues. So that's Eli Lilly's, those are rights that they purchased. So the opt-in mechanics are as follows. At the end of the last patient in the phase one, after the last patient in the phase one, we have a little bit of time to get them a data package, and then they have some time to review it and make the decision, and when they do, you know, the cost sharing kicks in. We expect the following next year, first half, an initial data release for VERVE-102, the Heart-2 trial, then in the second half, final data and the Lilly opt-in decision, because that's contingent on the last patient being dosed in the phase one. Got it. Okay. And the difference between the initial look and the final look, what's the difference there? I think the initial look will be several cohorts of data. You know, we already have two and some more, and it's really to get people. You know, we had this setback with 101, and you know, we really do want to show. Look, we're on track. We have a good product profile here, and then you know, we likely will continue to dose in the study, and the final data will have that additional number of patients, basically. Great. The patient population, how different is the 101 patient population versus the 102 population? And, you know, a couple of the safety issues, I think, were debatably not necessarily a result of the drug, but a result of the patient population that you were forced to study. Yeah, I think the patient pool, you know, remember this is in vivo gene editing, brand new as of a few years ago, a couple of years ago when we started. And we did start with a set of patients who I think had severe disease, advanced disease, coronary disease. And therefore, you know, some of the challenges could have been due to the underlying disease rather than the drug itself. What we moved to is patients with more moderate disease, less advanced disease. And we've done that in a couple of different ways, including incorporating screening tests, called a coronary CT angiogram, that can look directly at the heart arteries to see if there are blockages, and we're excluding patients who have pre-existing severe blockages. There are two patient groups that we're recruiting in or enrolling in, in Heart-2, both patient populations that require lifelong LDL lowering. One group is called heterozygous FH, that's a genetic disease I mentioned earlier. It's actually a very common genetic disease. There's about a million people in the U.S. with this disease, typically LDL cholesterol over 190 from early in life, heart attack at a young age and so forth. So that's one group. The second group is patients who've had a heart attack at a young age. They don't necessarily have that genetic condition of HeFH, but for a variety of different reasons, they've suffered a heart attack in their 30s or 40s, so-called premature coronary artery disease. So these are the two patient populations that are recruiting right now, and as I said, they're recruiting patients who have less advanced, more moderate disease, compared to 101. Great. And I think we've already talked about the duration of benefit that we've seen, you know, in the Heart-1 population. Any other safety issues that have come up at all, or is that just sort of the early dosing dynamic, that? Oh, for long term, yeah. No, that's actually the one interesting thing is that, you know, there's the safety issues that we saw with 101 were all in the post-dosing period in the first few days, acute. And then we've done long-term follow-up now out to 18 months and a few of the patients, some of the patients, there have been no, you know, additional issues beyond the acute time period. Got it. Let's talk about VERVE-201 and ANGPTL3 piece of. Yeah, so 201 targets a gene called angiopoietin-like 3. It's actually kind of similar to PCSK9 in the sense that it's been shown that if you turn it off, or if it's turned off in humans naturally, it leads to lifelong low cholesterol levels. People are protected from heart attack. It's actually people are healthy, even though they may not have this gene at all in the liver, and so it's a very good target. We are developing this target for two patient populations. One is a group called homozygous FH. These are patients who have very high LDL, like 500, 700, 800 from birth. It's a rare orphan disease. The second group is called refractory hypercholesterolemia. These are patients who take, who might be taking a statin and a PCSK9, and they still have too high cholesterol. And then it's been shown that ANGPTL3 inactivation in either of these two populations lowers LDL by an additional 50% on top of their existing medicines. So that's those are the two groups we're developing in. We announced that we dosed our first patient with VERVE- 201 targeting ANGPTL3, just with this last earnings release. So that program is on track and it's really great to have these two products simultaneously in the clinic dosing. There's a little bit of a profile choice that you needed to make between targets, right? There's ApoC3 and then also ANGPTL3. Why one versus the other? Yeah, so both ApoC3, which is another target that has very nice genetic validation, and ANGPTL3 affect triglycerides. The reason we chose ANGPTL3 over ApoC3 to go after for our second program is that ANGPTL3 not only affects triglycerides, but also lowers LDL quite powerfully. And LDL is the best validated surrogate marker in all of cardiovascular disease. As I mentioned earlier, the whole company's built on this insight that if LDL cholesterol was really low lifelong, you wouldn't get a heart attack. So that's the reason to go after ANGPTL3. It affects both LDL and triglycerides. Next steps for VERVE-201, you've dosed your first patient, but in terms of accumulating enough data to. Yeah, so we're guiding to data next year for 201. Yeah, and the approach is similar utilizing GalNAc. Yeah, so that's one of the key things is that once 102 we have the data in the first half of next year using this GalNAc lipid nanoparticle, we de-risk the delivery system as well as the cargo. And so it really unlocks the rest of the pipeline because 201, for example, uses the same GalNAc LNP delivery system, uses the same editor, it just switches out the guide RNA. And then if you go to the next program, Lp(a), it'll use the same GalNAc LNP delivery system. So, it's really, I think next year is a really momentous, very, will be a very eventful year for us because it not only has implications for our lead asset, but also for the rest of the robust pipeline. Yeah. And then in terms of what's new, as we think about Lp(a), what are the unique, you know, learnings that you've made on the preclinical side? When might we learn? Because my understanding is Lilly has a little bit more control over the program, but, you know, just interested to know how that program is advancing, maybe without necessarily disclosing what. Yeah, no, we're super excited. Good, as are a lot of people because there's other modalities being developed. But I think, so this program is structured, the relationship with Lilly is structured different than the first two where they literally kind of have what we characterize as minority product rights. Whereas this Lp(a) relationship is something we struck with them directly a couple of years ago. And here we are doing the research and development through phase one. They're paying for all of it. And then at the end of phase one, Seamus, the program, the Lp(a) program transfers over to them. At that point, we get royalties and milestones. We do have the ability to potentially opt in to a profit share, but the base case is royalties and milestones. This program, as a result, the decisions about public disclosure are a joint decision and we really have not shared much to the public on the preclinical data or the editor we're using actually, which is distinct from the base editing approach we're using for the first two products. All we've said is that we're making really good progress. We did receive a preclinical milestone payment earlier this year and we expect more next year. I think the target, you know, I think for me, the story in cardiovascular disease over the next couple of years, few years, let's say next decade is going to be a series of high value targets of deep, you know, people have a lot of conviction in. For each of these targets, let's say Lp(a), there will be different options. Lilly is developing a pill against Lp(a). They're developing an siRNA against Lp(a), and then they're working with us to develop a gene editing option, and ultimately, like it'll, you know, all three of those options may be out there all from Lilly, and people will have choices, patients, providers, and hopefully payers as well, and so that's, I think, the future of cardiovascular medicine where, and people will pick, you know, some people will prefer a one and done, some people will prefer to take a pill every day, and so we're excited that Lilly shares this conviction that we have in these targets, and excited to work with them. Great. And in terms of just if you were to predict, put on your KOL hat, if you were to predict the likelihood of Lp(a), where, you know, are you in this, you know, complete suppression of Lp(a), partial suppression? I would argue that it seems like if you're going to edit it, you kind of want to be on that complete side, but are there any risks to that at all? I'm generally, you know, again, generally of the principle as low as possible for as long as possible for each of these things. LDL cholesterol, remnant cholesterol, which is kind of what's in triglyceride-rich lipo proteins and Lp(a) cholesterol. So, yeah, I think I'd like to have the suppression as deep as possible for as long as possible. Great. You know, two final questions. The partnership with Vertex, similar to the Lp(a) situation with Lilly, so not a lot to talk about there and perhaps even more secretive. That's right. Okay. Fair enough. And then lastly, just sort of the financing of the company, how much cash, your cash runway, always. So we ended the last quarter with $540 million. That takes us a runway into 2027. So we're in good shape to get through what should be a very eventful year next year, that unlocks not only PCSK9, but for the rest of the pipeline, and more milestones in 2025 as well, 2026 as well. Fantastic. Well, Sek, thank you so much for joining us.