Well, good morning, everybody. Thanks for joining us here at Guggenheim's SMID Cap Biotech Conference. We sort of target companies below the kind of $12 billion threshold for this conference because these tend to be the companies that actually have the highest returns in biotech overall. So it's a great opportunity to be joined here this morning by Verve Therapeutics. Sekar Kathiresan, Co-founder, Chief Executive Officer, is with us today, and in the audience, Allison Dorval and Jen Robinson are with us. But you know, maybe, Sekar, just to kind of kick us off, we've got obviously some exciting data and a lot of events coming up this year for Verve in particular. But maybe just remind people the Verve story, and also you know, it's really one of the opportunities that we see for investors to actually make you know, meaningful returns this year. Maybe you can kind of lay out the story and then we'll jump into Q & A. Yeah. So Verve's mission is to really change the way cardiovascular disease is treated, move it from chronic care to one-time therapy. So think one-time treatment, a lifetime of benefit. We're doing that by addressing the three main drivers of atherosclerosis. This is LDL cholesterol, remnant cholesterol, and Lipoprotein(a). So these are the three carriers of cholesterol in the blood. And we have a target against each one of these three drivers, PCSK9, ANGPTL3, and LPA. And we've made really good progress in the pipeline, again, against each of these targets. So for the PCSK9 program, we have two products, VERVE- 101 and VERVE- 102. We're currently focused on 102, and we have a phase one data readout that we're guiding to in Q2. So coming up for that product, and we'll talk more about that. For VERVE- 201, targeting ANGPTL3, that product is actually in the clinic as well. We just dosed our first patient in Q4 last year, and that'll dose escalation will be progressing, and we're guiding to a program update toward the end of the year, this year. And then exciting, we just announced development candidate for VERVE- 301, targeting LPA. This is a collaboration with Eli Lilly, and that product is making really good progress. And so, really nice progress across the pipeline. We have a couple of more assets as well. And I think 2025 is gonna be quite a milestone-rich year for us. And we'll have a chance to talk about some of those as well. Yeah. Great. And you know, maybe just to sort of orient people to the PCSK9 portion of the story. You know, yesterday Amgen reported results with their own antibody, which is a monthly dosing regimen. You know, saw 43% year-over-year growth, well north of a $2 billion category now, probably headed to multi-billion. You've talked about the inclisiran growth opportunity at Novartis as we're starting to see that convert to a billion-dollar product. You know, the surgical sort of comparison, I think, is value added here. So can you talk a little bit about that, that sort of one-and-done opportunity? Yeah. I think, I think another way to kind of think about this is that we often get asked, you know, there are a lot of options on the market right now to lower cholesterol. So do you really need something new and why do you need it to be a one-time therapy? I think that there are a couple of ways to think about this. One is, first of all, the scope of the market is very large, and highlighted by the fact that the PCSK9 as a class is expected to sell, you know, north of probably $5 billion this year, and that's the three agents, and the one that's growing the most, 100% year-over-year, is actually inclisiran, you know, which is dosed twice a year, and so, really the main differentiating factor there is durability, and that's what patients are preferring. So the class is growing and it's already sizable, but that overall represents less than 10% of eligible patients are actually on these medications. So you can just see all the white space that's still there, and when you think about, you know, why one-and-done, it really comes down to the fact that the majority of patients, who get started on a cardiovascular medication are no longer on them at one year. Yep. You know? And that's a range of reasons. It's not just adherence. It's cost, it's access, it's, you know, all the things that go with having to take a daily pill or inject yourselves regularly for a long time. And we really think that, you know, a one-time therapy that gives you durable LDL lowering, you know, is gonna be a very differentiated product in this space. And the surveys, the patient preference surveys kind of point that out. Yep. So, and we talked about this before, but if you ask patients who need, require lifelong LDL lowering, you know, you have the option of a daily pill, twice a month injection, twice a year injection, one-and-done. The responses are as follows. About 40% will say they prefer a daily pill. About 14% will say twice a year, like inclisiran. 4% will say twice a month, like Repatha. And then a full 35% of people prefer a one-and-done. So there's a remarkable openness among patients. Similar openness among physicians, actually. And we've done physician surveys that kind of highlight the same concept. Yep. I think there's a lot of opportunity here, you know, once we develop this product. Great. So the prioritization of VERVE- 102 over 101, I think for folks familiar with the space, it's kind of obvious. But maybe you can just sort of explain what work you've actually done and what we're, you know, sort of anticipating to see, you know, hopefully at the, I think it's the second quarter timeline. Yeah. VERVE- 102 and VERVE-1 01 differ only in the delivery system, the lipid nanoparticle delivery system. They have the same cargo, the same editor, same guide, and what we're testing 102 right now in the Heart-2 trial. From 101, which we tested last couple of years, we learned a lot. We learned that base editing can work in humans. We were the first to show that, for in vivo base editing. We learned that you can reduce PCSK9 80%-90% by doing a one-time treatment. And as a consequence, get LDL down 50%-60% and do it durably. You know, we've been able to show that after the one-time treatment, LDL can come down 50%-60%, and 18 months later, the LDL is still down, that same amount. Yep. So all of that we learned. Now, what the challenge we faced with 101 was that the delivery system, the lipid nanoparticle, and specifically one of the components, led to transient rise in liver function tests and in one patient, drop in platelets. And we paused 101 based on those results and have prioritized 102. And we feel 102 will essentially retain the efficacy and durability we saw with 101 because it has the same cargo, but avoid the laboratory abnormalities because the lipid nanoparticle has been switched out. And the key components that are different are the ionizable lipid is different in 102. It's a new ionizable lipid that we sourced in from Novartis. And then the second is, we've added this GalNAc targeting ligand that should make it even more specific to the liver. So those are the two changes. We did disclose as of October 29th of last year, we had dosed seven patients, and we were not seeing the laboratory abnormalities with 102 that we saw with 101, and then we're guiding to, as I said, data disclosure for 102 in Q2, you know, minimum 10 to 12 patients. Each patient will have a minimum of 28 days follow-up. We'll have LDL safety and PCSK9 values as well. Got it. That's in Q2 of this year. Great. And in terms of the GalNAc, just in, you know, there was a decent amount of variability in the LDL lowering in the patient population that you studied with 101. In terms of the sort of consistency of the data, is the GalNAc, you know, likely to increase from your perspective, the consistency of the data in terms of the LDL lowering and sort of the, because of the specificity to the liver? Yeah. Actually, the main reason we invented or developed our proprietary GalNAc and put it onto the LNP was to address the patient population we're going after, heterozygous FH. Yep. I should mention Heart-2 is being tested in two groups of patients who require really LDL lowering for decades, deep lowering for decades. Those are patients with a genetic form of high cholesterol, heterozygous FH, and/or patients with premature coronary artery disease. Patients who've had a heart attack in their thirties, forties, fifties. Those are the two patients being studied in Heart-2. If you look at the heterozygous FH patient population, a fraction of them will have mutations in the LDL receptor gene. Now it turns out standard lipid nanoparticles, ones that don't contain GalNAc, the ones that most people are using, actually get taken up by the LDL receptor into the hepatocyte. Yep. In the patients who are deficient in the LDL receptor, there may be some challenges in the lipid nanoparticle getting in and therefore some variability in response. Got it. But with the GalNAc on board, the lipid nanoparticle can get in through an LDLR independent mechanism through the GalNAc receptor, ASGPR. Therefore, this VERVE-102 LNP should be able to have equal efficacy in patients with the mutation and versus not. Okay. Great. And then when we think about the upcoming data, can you just remind us the time point where, you know, sort of second quarter result will be presented? And then, you know, as we go beyond that to sort of the opt-in timeline for Lilly, what additional data would potentially be available at that point in time? Yeah. So there I would think about 102 in terms of there are three milestones for the year. The first is the Q2 data release, and that'll be across three dose levels, 0.3 mg/kg, 0.45 mg/kg, and 0.6 mg/kg. As I said, minimum 10 to 12 patients, and everybody will have at least 28 days of follow-up. And I mentioned the end points. That's the first item this year for 102. The second item will be the full dose escalation data, and that'll be in the second half. And then, probably the last to come will be the Lilly opt-in decision. And just to walk people through that, so Lilly has the right to opt into the program. The way that right is structured is we'll end up pulling together the entire dose escalation data, along with a development plan beyond phase I and a budget, present that to them. Then they'll have some time to mull that over and make a decision on the opt-in. We expect them to make that decision in the second half of the year, probably toward the end of the year. Okay. Great. And then, you know, when we go back to the AHA dataset, can you just remind us, you know, that patient population was very, very sick and it was at, you know, sort of the driving force of the FDA's requirements. How does this VERVE-102 dataset compare, you know, relative to that patient population that actually was quite sick? Yeah. We moved to less advanced patients. I think one of the challenges with an open label study without a placebo arm is, you know, are any events that are happening, safety events, due to the underlying disease, the sickness of the patient population or due to the drug? And that's difficult to sort out when you're starting with the sickest of the sick. And we got into a little bit of that with 101. Yep. And so the way we modified that for 102 is, we're enrolling patients that are less advanced in their cardiovascular disease course. They require lifelong LDL lowering, but they're just not as far along in their CV disease course. The main way we did that was adding in a coronary CT angiogram, a non-invasive test, to make sure that patients don't have severe blockages, obstructions in their coronary arteries coming into the study. Got it. Okay. Great. You know, in terms of just sort of the timelines, you know, I think you've talked about where the patients are dosed, you know, the doses that are being explored and tested. But in terms of the sort of exposure necessary to achieve maximal LDL lowering, is 0.65 really where you would expect the end to be, or is that sort of the limit relative to the, you know, risk of minor LFT abnormalities or anything like that? What's the sort of upper limit of the dose range? I think that's what we're exploring, right? Yep. With the dose escalation. But I think another way to think about this is what is our target product profile here? Yep. You know? And I think our target product profile is to have the PCSK9 come down anywhere between 60%-80%, and the LDL, as a consequence, will come down between 40%-60%. Yep. I think a key benchmark for us is the product on the market with the longest duration of action, because our key differentiating factor, right, is one time for a lifetime. So it's really the length of the duration of action, right? What out there right now is close to a lifetime? It's really inclisiran, which is every six months. Yep. Right? So what's inclisiran performance in these two patient populations, HeFH and ASCVD? Well, inclisiran lowers LDL compared to baseline in their phase III for HeFH by 40%. And it lowers it for ASCVD patients by 50%. So that's kind of our bogey. Okay. for, you know, and then everything above that I think would be great. Great. And then, you know, as we think about the sort of broader opportunity, the commercialization story here, you know, there's two things that I think investors care about. How big do the trials need to be? You know, as you sort of advance into phase II and phase III, and then, you know, the second iteration of that is gaining access to that ASCVD patient population. You know, how should we think about that trade-off of the availability of lots of generics, lots of competitors, things like that? HeFH seems like almost like a slam dunk, but I'm not gonna. Yeah. I don't wanna, I'm not implying that. Yeah. We're starting with HeFH. That itself, that patient population, I think it's underappreciated how serious an illness that is. These are patients who have heart attack in their thirties and forties. Again, cholesterol high from birth. It's not. You can't fix it with lifestyle typically. And so it's a serious disease and there are three million patients just in Europe and U.S. alone. Yep. So very prevalent disease. And so it's a huge opportunity, market opportunity, for with this kind of product. And that's where we're starting. And then you'd like to, you know, ultimately get to ASCVD as well. In terms of for HeFH, the trial sizes are very manageable. And just take inclisiran. inclisiran's phase three, first of all, it's an LDL endpoint, not outcomes. LDL endpoint. Yep. In fact, there's never been an outcome study done or required in HeFH patients, so LDL endpoint and the sample size was about 400, maybe 500, so very manageable, and that's our first, first indication. Okay. And then even for ASCVD, LDL has been the endpoint. The sample size has been a bit larger, a couple of thousand people with LDL as an endpoint. But again, quite manageable. I think one point I wanna make on the commercial is, you know, gene editing, gene therapies, you know, the sentiment on commercial opportunity for these kind of products is down, based on the fact that people assume it's millions of dollars a dose. And where there are alternatives, it's challenging to kind of get onto the marketplace, get adoption. I think we're quite differentiated actually from the run-of-the-mill, gene therapy. A couple of reasons. Okay. One is we're not gonna be millions of dollars a dose. Yep. You know, we have lots of patients. It's not a rare disease pricing. We don't need to resort to that. The second is the cost of goods. You know, many of the other therapies, cell therapy or gene therapy, have to be millions of dollars a dose because it often costs millions of dollars to actually make this stuff, you know? Yep. You know, for us, it's actually, you know, our best competitor, the product that looks most like us is a COVID vaccine. Yep. It's mRNA packaged in a lipid nanoparticle. We know that about 100 micrograms of that stuff can be made for like a few dollars, $3-$4. Now we're not, we're gonna be giving more like 50 milligrams, but if you just multiply up, you know, you're basically talking low thousands cost of goods. Yep. With that kind of cost of goods, you're gonna have a great margin at a range of price points. Yep. You know, and I think that's a unique opportunity we have, flexibility that we have that others won't have. Got it. So lots of patients, manageable cost of goods, lots of flexibility I think in terms of pricing down the road. Great. Let's talk about the VERVE- 201, ANGPTL3. You know, the opportunity that you see there, you know, and are there opportunities to combine the two at some point? Yeah. We see three opportunities for ANGPTL3. Remember, it attacks remnant cholesterol. So it's a cholesterol focus, but there's also the high triglyceride, severe high, severe HTG indication. But on the cholesterol side, it's really two groups of patients. One with homozygous FH, so really high cholesterol. And this is a unique mechanism that works in those patients. That's a rare orphan disease. But then there's a larger group of patients called refractory hypercholesterolemia who basically, despite being on a statin and a PCSK9, still have LDL that's too high. That's actually several million people actually in the US and Europe. So that's another opportunity. Again, LDL-based, cholesterol-based endpoints, that's where we're focused on ANGPTL3 initially. And then I think we have the potential to go after SHT, SHTG down the road as well. Great. And then, you know, just update us on where we are from a recruitment perspective, for that study. Yeah, so 201 started in patients last year. Yep. And there's a dose escalation ongoing. Importantly, it uses the same GalNAc lipid nanoparticle delivery system as 102. Yep. It uses the same editor as 102. All that's been switched out is the guide RNA. So quite modular. So really we, with 102, we're de-risking the rest of the pipeline in some sense, specifically on the delivery. So 201 in patients now, we're dose escalating, we're guiding to a program update toward the end of the year, and that could be a data update depending on enrollment. In that context, what would you hope to show? What's your sort of comparator, asset? Is it the Regeneron antibody, that's sort of a best, you know, sort of comparator targeting ANGPTL3, or is there some other metric? Yeah. I think it would be probably the siRNAs that have been developed by Arrowhead and Lilly, and they lower ANGPTL3. Our TPP would be we want it to be more than 80% lowering. Okay. We expect that to translate to greater than 40% LDL lowering. Got it. Okay. That's now on top of statin plus PCSK9. So it's really quite remarkable. Yep, and then, maybe just to wrap up, Lp(a). I think we've all been, you know, waiting for Novartis to update us on event rates and things like that. But, you know, how you think about the opportunity for Lp(a), you know, there's a lot of speculation around, is it a threshold benefit? Is it really sort of reflective of maximal lowering of Lp(a)? But, you know, if you were to sort of design a study targeting Lp(a) specifically, how would you think about kind of isolating that risk to some degree? What I'm excited about is this is a molecule that is, I think, uniquely appropriate for a one-and-done, where it's almost all of the blood level is you inherit it. It's basically just a bad actor. There does not seem to be any positive thing that comes from it, and so you just wanna get rid of it if that's been the cause of your heart disease. Okay. and our timeline for development, I think, coincides beautifully with all this other work that's being done across the three trials to sort out exactly the questions that you're talking about. How much LPA, LPA lowering do you need for how long, in what patients, will translate into what degree of CV benefit? Yep. That's gonna be addressed over the next three years across three trials in over 30,000 patients. And that information will coincide beautifully, I think, with when we start our phase I, two, three, and will inform how we take this product forward, which has the characteristic of a one-time treatment, you know, dramatic lowering of LPA and durable lowering of LPA. Yep. And, you know, when you sort of think about Lilly as a prospective partner, you know, maybe just remind us the ownership rights that you have within the context of the Beam rights that they acquired, and then, you know, how that differs from the Lp(a) program? Yeah. So we have two different structures in terms of the Lilly collaboration. For the first two targets, PCSK9 and ANGPTL3, there are these opt-in rights that I mentioned. They have the ability to opt in at the end of the dose escalation portion of the phase one, and if they do opt in, when they opt in, it'll be they pay for a third of worldwide development cost from that point onward. And in return, they get 50% of U.S. profits. The other 50% of U.S. is us and 100% XUS is us. And interestingly, PCSK9 as a class, unlike other cardiovascular medications, it's now looking like almost 50/50 U.S. and XUS. Right. So it's quite, it's a little bit different. So the XUS rights are very valuable here. We have majority rights, they have minority rights. Importantly, we control development and we book revenues. Again, this is not the standard big pharma. Right. Biotech relationship. It's because they purchase these rights from Beam Therapeutics who have been the holder of these rights. So that's how the structure is for the first two targets. And then LPA is actually something different. It's structured much more like a standard pharma biotech where we're doing all the research, they're paying for it. The program turns over to them at the end of phase one. We, and at that point, we get royalties and milestones. We could convert it to a profit share if we wanted at the end of phase one. But that's the deal. Okay. Got it. Got it. So, lots of exciting things going on. We have to wrap up, unfortunately, but say thanks so much for joining us and great, and good luck with your second quarter. It should be a terrific reveal. Thank you. Yeah. Yeah. Great. Thanks so much. All right. Thanks.