Morning, everyone. Welcome back to the Cantor Fitzgerald Global Healthcare Conference. My name is Rick Mankowski. I'm a biotech analyst here on the Cantor team, and with us today, I'm very pleased to be hosting Sekar Kathiresan, CEO of Verve Therapeutics. Welcome, Sek. Delighted to be here, Rick. Thank you. All right, so to begin, I'd just like to level set for our audience. Could you give us a brief introduction to Verve and also the company's approach to developing one-time treatments for cardiovascular disease? Yeah. Verve is looking to solve atherosclerotic cardiovascular disease or ASCVD, which is basically blockages in the heart arteries that come from blood cholesterol accumulating over time. It's been pretty clear from a lot of human genetics research that if one's cholesterol, blood cholesterol, is really low lifelong, it's actually very hard to get a heart attack, get these blockages. What we're trying to do is develop a new treatment option for patients, which is essentially like a molecular surgery. It's like a one-time procedure leading to permanent lowering of blood cholesterol as a way to treat heart attack and ultimately avoid it altogether. And the technology is really turning off cholesterol-raising gene in the liver using CRISPR-Cas9 kind of technology. Specifically, we're using base editing, and we're making a single spelling change in DNA of the liver to turn off the PCSK9 gene. That's for our first target. By doing that, with a one-time treatment, this is an intravenous infusion treatment, one time, few hours infusion, the gene gets turned off, the blood cholesterol comes down, and in non-human primates, three years later, the blood cholesterol is still 60%-70% lower compared to baseline. In humans, we've started to do phase 1 work, and we can talk more about that. The approach is really one-time therapy, permanent lowering of blood cholesterol to treat heart attack. All right, great, and before we get into some of the clinical data and most recent updates, I'd like you to also talk about specifically the heterozygous familial hypercholesterolemia market. Your lead program is investigating VERVE-101 and VERVE-102 in that indication. So, could you just talk a little bit about the size of the market, the level of unmet need here, and what the treatment landscape currently looks like? Yeah. So, there are a group of patients who have very high cholesterol from birth. They have this label of either severe hypercholesterolemia or heterozygous familial hypercholesterolemia, HeFH. This is inherited, and their cholesterols are, you know, sky high, like over 190, 200, that level. It's a very morbid disease. About half the patients, the first manifestation is death. If not that, then they have heart attacks in their thirties and forties. And what they need is lifelong cholesterol lowering. There are treatment options right now to lower cholesterol, either daily pills or injections of varying frequency. But the unmet need here is that the majority of patients who have this sky-high cholesterol are not actually on any of these therapies. And for those that are on therapy, they, most of them are not at goal. Only about 2% of patients are actually at goal worldwide with heterozygous FH. And it's actually a fairly common genetic disease, about 3 million people in the U.S. and Europe. Prevalence is about 1 in 250. So as far as genetic diseases go, this is pretty common. So what we're hoping to be is a functional cure for these genetic patients with sky-high cholesterol. And the unmet need, as I mentioned, is there because the current options are not really either being used or adhered to. All right, understood. Yeah, so we can dive right into the lead programs. There are two lead programs in HeFH, VERVE-101 and VERVE-102, both in phase 1 trials. You know, some of the more recent updates was the development of VERVE-101 was actually paused back in April after grade 3 adverse events emerged in the trial. So first, I was hoping to talk about could you please contextualize that pause in context with the development of the programs, and then we can move on to some of the differences between VERVE-101 and VERVE-102? Yeah. So maybe take a step back and kind of just walk you through that development and the rationale that we had to develop two products against the same target. So when we started the company in 2018, there was a range of different risks 'cause we're trying to develop a whole new approach, a new treatment modality. One of the risks, of course, is the biology of the target, and that we, you know, tried to take off the table by picking targets that had really wonderful human genetic evidence, that it's safe to turn off the gene, and that it would be efficacious. And there was also prior human pharmacology, and PCSK9 met both of those criteria, so we really felt comfortable on the biology risk. But then, there are kind of two technology risks. One is editing. Can you actually edit in the liver to turn off a gene, particularly with the base editing approach? And the second was, can you get the editor to the liver? And how would you do that? So kind of delivery. And so for both of those technology risks, we did evaluations of various options. For the editing, we actually looked at a couple of different editing options, base editing versus standard CRISPR-Cas9, and ultimately selected base editing because we felt it had a safety advantage in terms of avoiding translocations, avoiding double-strand breaks. Then on the delivery side, there had not been a lot of experience actually delivering large molecules, large mRNA molecules, to the liver for editing using lipid nanoparticles, for example, as a delivery system. So we ended up actually having two options, two different delivery systems that we developed: one that's being used in 101, and then the other being used in VERVE-102. So our first two products, both target PCSK9. They both have the same base editor, the same guide RNA, but they differ in the delivery vehicle. So the first one we took forward, VERVE-101, we treated 13 patients in the Heart-1 trial, 7 of them at potentially therapeutic doses, and we saw very nice efficacy. We were able to show, for the first time, that in a human being, you can actually make a single spelling change in nearly every liver cell, so the concept really, you know, worked. And we saw, you know, 60% LDL lowering, 80%-85% PCSK9 lowering, again, suggesting that it is... We're editing every hepatocyte, nearly every hepatocyte. And then, there was durability, and I mentioned to you earlier that there's durability in non-human primates out to three years in our preclinical data after the one-time treatment. In the humans, we saw durability already out to nine months. So it was efficacious, it was durable, but we had some laboratory changes at the time of the acute infusion of the lipid nanoparticle, and those were elevations in liver function tests and also a drop in platelets in one case, grade three in one situation. Those laboratory changes were reversible. They kind of got back to normal on their own. They did not have any clinical problems associated with them. Despite that, we ended up pausing the one oh one trial to better understand what was going on, and also because we had this other option, this one oh two program, and that was ready to go into the clinic. Our hypothesis as to why we saw these laboratory changes, it really centered on that delivery system, that lipid nanoparticle delivery system, and particularly the lipid, the key ionizable lipid from that delivery system. What one oh two did is switch out that delivery system. It's the same editor, same guide, it's a different lipid, and it's a different, targeting, it's a targeting ligand has been added as well, a GalNAc targeting ligand. We can go over the differences in more detail in a minute. But, we have a lot of confidence that this new product, that is being tested in patients now in the Heart-2 trial, in a phase one, is gonna retain all the efficacy that we saw with one oh one, because it has the same editor and the same guide, but avoid the laboratory safety changes that we saw. And why do we think that? Two reasons. One is, we've tested in non-human primates and other preclinical models, both products, and we do see better tolerability for one oh two than one oh one on these parameters. And then second, the lipid that we're using in the second program has already been tested by another company in over 100 patients, and they're not seeing any significant changes in terms of liver function tests or platelets. So that human evidence and our own preclinical evidence gives us confidence that one oh two, again, will retain the efficacy that we saw but avoid the two laboratory abnormalities. All right, great. So just to be clear, for the VERVE-102 program, the LNP there, the lipid composition is different than VERVE-101, and also, there's the GalNAc conjugation to target- That's right ... the liver. That's right. Great. A typical lipid nanoparticle, just to get everybody up to speed on that, there's the mRNA, which is for the editor, and the guide RNA. Those are the two drug substances, and those are packaged in a little lipid ball, and that lipid ball typically consists of four components: what's called an ionizable lipid, a PEG lipid, cholesterol, and phospholipid. The cholesterol and phospholipid is pretty standard. You know, and pretty much the same in almost every lipid nanoparticle. The two key differences typically are the ionizable lipid and the PEG lipid, and both of those components are different between 101 and 102. Then, for 102, we've actually added a fifth component to the lipid nanoparticle that's proprietary to Verve, and that's the GalNAc. It's a carbohydrate that basically is a liver-targeting ligand, essentially, because it binds to the ASGPR receptor that's on the surface of liver cells. It's similar to the GalNAc that's been added to siRNA, for example, as a conjugation. But, I mean, in our case, we actually add it to the surface of the lipid nanoparticles, so kind of sticking out on the surface, and it really allows it to be targeted to the liver. So these are the key differences between one oh one versus one oh two. ... Got it. So in the preclinical work that's been done around both of these lipid nanoparticles, could you maybe go into some of the differences you've seen between the GalNAc conjugation and the non-GalNAc conjugated LNPs, whether there's differences in potency you've seen in preclinical studies or anything else? I think the main thing to emphasize is really, is really the tolerability, I would say, you know. We basically feel that we can get to much higher doses with 102, without seeing the liver or the platelet changes, and so that's what we are observing in our preclinical models. Those third-party trials that I mentioned, they've been able to get to roughly 0.7 mg per kg, 1 mg per kg dosing with this ionizable lipid, and that's the one that we're using in 102. I got it. So the company was able to generate a rather impressive clinical data set, back at, the American Heart Association last year in that presentation. And there is some validation there, as you were saying, for the base editing technology and somewhat de-risking the mode of editing. Could you maybe talk about some of the learnings from that initial clinical data set and what that means for the study of VERVE-102? And I guess, specifically right now, I'm thinking of, you know, the dose escalation, what may be an effective initial dose there, the number of patients that will be treated, and any other learnings from the first study. Yeah. I mean, I can walk you through the learnings from that first study has shaped the Heart-2 trial, which is the trial that's ongoing now, testing VERVE-102. Kind of walk you through that design. So it's a single ascending-dose design, dose escalation, several dose levels. It's pretty flexible as to how many, but let's call it, you know, three or four dose levels, and roughly minimum three patients at each dose level. You can dose expand up to six, nine, it's pretty flexible. So roughly three patients minimum, let's call it each of four dose levels, so roughly 12 patients across the four dose levels. And, you know, we're dose escalating now, and our goal would be to have at least an interim data set in the first half of next year. Now, the patients that are being treated are those. There are really two groups, actually. One is a group of patients who have the high cholesterol, very high cholesterol from birth, the heterozygous FH group. And then the other, we added to 102, this trial, new trial, is patients who have had a heart attack at a young age. The rationale for these two groups of patients is these are both groups of patients who need lifelong cholesterol lowering, and where our approach of a one-time therapy, lifelong cholesterol lowering, would be particularly attractive. You know, somebody who's had a heart attack at age forty-five is facing, like, thirty years of LDL care, and our current model of daily pills, intermittent injections, puts a very heavy treatment burden on patients. And the reality is that the majority of patients are not on any of these medications. I think this is a surprise to a lot of people 'cause we get a lot of questions about: "Look, there's lots of options out there to lower cholesterol. Why would anybody need anything new?" I'll give you a very simple stat. We were just looking at this the other day on discontinuation rates for the injectable PCSK9 agents. So believe it or not, one year out after starting, let's say, a monoclonal antibody targeting PCSK9, about 45% of patients have discontinued. They're no longer on the agent at all, for a variety of reasons you can come up with, and so that means that somebody who's had a heart attack at age forty-five, they're on the medicine for a year. What about the other twenty-nine years of their, hopefully, life expectancy? They're probably not getting treated well, you know, so anyway, getting back to the trial, these are the two patient populations. Single ascending-dose design, three to four dose levels, minimum three patients in each dose level. Got it. Another thing I wanted to touch on was, in the initial Heart-1 study, I believe, based on FDA guidance, Verve did recruit basically the highest-risk patients that were available for the study, and it made interpreting the safety a bit challenging, you know, based on how high-risk these patients were at the beginning. Were you able to recruit patients that were a little bit lower on the risk scale for the Heart-2 study? Yeah. That is a change that we've made, or modification, is that, you know, this was a brand-new technology a couple of years ago, and we ended up, you know, essentially recruiting the sickest of the sick for this approach initially, and in an open-label trial, that does make, you know, events that would happen because of the disease, underlying disease, it makes the safety of the drug more challenging to interpret. What we've moved to is patients with less advanced disease for Heart-2. And we've done that in a couple of ways, some protocol changes, but also, we've been able to screen with some tests, like a coronary CT angiogram, which is a non-invasive way to look at the heart arteries, to make sure that there's not pre-existing, really severe blockages that would cause problems in the period after dosing. So those are the changes we've made to move to less advanced patients. ... All right, so you're guiding towards an interim readout in the first half of 2025. Have you disclosed how many dose levels we're expected to see in that readout? We've not refined that just yet, yeah. Okay, but back to the question about LNPs. So it's my understanding that any sort of a safety event associated with an LNP happens fairly quickly after administration of the drug. So I guess, in this initial readout, could you maybe speak to the level of confidence you'll have around the safety of the VERVE-102 LNP after this initial interim readout? Yeah. So the safety abnormalities that we saw, the laboratory abnormalities in the first trial, all occurred within, you know, 24 hours of dose, 24 to 48 hours of dosing. The LFT changes, the platelet changes, are acute, as you point out. You know, the initial observation period of a few days to a week will give us a good sense of that. We presented last time in the Heart-1 trial, I think, efficacy data at 28 days for everybody. There was durability data with varying degrees of follow-up, based on when they got into the trial. I think our output in the first half of next year will likely take a similar approach. Okay, great. And thinking about the next steps for the program, do you think that maybe after the initial interim readout, that will be sufficient to determine which candidate to bring forward into further clinical studies or Phase Two studies, or do you think that a longer-term readout would be needed for that? I think you know, we would want to complete the dose escalation before moving forward. But our guidance right now is we'll be in a position to pick a dose to take forward to phase two and initiate that phase two next year. So second half of next year. So basically, the phase one will be complete to the point where we'll be able to take a dose forward next year. Okay, great, and if we could touch on the phase two trial, to the extent you could talk about this, since I know we're still in phase one, but how do you see a phase two trial being run? Would it be similar to this trial, in that it would be a single-arm trial? How large of a patient population do you think you'll need to evaluate it in phase two? Just if you could comment on that. Yeah, I think we are actively designing that phase 2, as you can imagine, right now, and so some of these questions are not yet resolved, but I think one model would be placebo-controlled, and you know, one or two dose levels, and a size roughly you know, 50 to 100 patients, something like that. Okay. Great, and, VERVE-101, is still on pause. What are the next steps for that program? Are we expected to see any updates there in the near term? I think the, you know, one update that we get asked about is durability. You know, can you show us that, you know, the treatment that you gave, you know, similar to the non-human primates, do you have durability out to a year and, you know, 15 months, something like that? So I think we do hope to share that kind of information coming up, to really show, yeah, this is likely to be a one and done, this approach, unlike some of the other approaches. Here, with editing in the liver, even though it's... You know, the liver can regenerate. We are basically editing, we think, the cells that are regenerating so that the source of regeneration, so that basically, as they divide, they're carrying forward the edit, and this is truly gonna be durable for a very long time. So we wanna show that kind of durability data from one-oh-one. All right. Great, just a couple more questions on the PCSK9 program before we move on. So there's a partnership with Eli Lilly here. They have the ability to opt in to development of VERVE-101 or VERVE-102. Could you maybe just elaborate on the option they have to co-develop and co-commercialize, and also, at what time point would they potentially opt into the program? Yeah, so, last year, Eli Lilly purchased a minority product rights that had been held by somebody else. That was Beam Therapeutics. And these rights, that they purchased, for the PCSK9 and ANGPTL3 products, can be characterized as follows: They have the ability to opt in at the end, last patient in phase 1, after that. And if they opt in, they basically are responsible for a third of worldwide development costs, from that point onward, and in return, they get 50% of U.S. profits. The other 50% of U.S. profits is us, and then 100% of ex-U.S. is Verve. Really, these are minority product rights that are held by, Lilly. In addition, we book revenues, and we control development. We were really excited to have Lilly take on this from Beam, 'cause we could not think of a better partner for long-term development in the cardiovascular space, cardiometabolic space, than Eli Lilly, and it's been wonderful so far. All right. Fantastic. If we could shift gears a little bit, I'd like to talk about VERVE-201 and homozygous familial hypercholesterolemia, which I will probably just call HoFH from now on. So yeah, this product is the second product being developed. I was hoping you could just talk a little bit more about the market and the stage of it, of development. Yeah, so, our first program targets PCSK9, the second program targets ANGPTL3, the third program targets LPA. We have another program that is undisclosed target, and then the last one targets a liver disease. That's a collaboration with Vertex. And I think one exciting aspect of where we are right now is that with the de-risking of the delivery system, this GalNAc lipid nanoparticle delivery system that we're using in 102, in the next six to nine months, that should unlock the rest of the pipeline because the rest of the pipeline uses the editing system that's been de-risked, or related to editing systems, and we use the same GalNAc-LNP. So that's, I think, a really nice thing to look forward to, hopefully, in the next 12 months or so. In terms of the second target, ANGPTL3, this is a liver target. This is a gene that raises blood cholesterol and triglycerides, and turning off this gene lowers blood triglycerides and blood LDL. The product is intended for kind of two groups of patients, patients who have what's called refractory hypercholesterolemia. So these are patients who have still uncontrolled cholesterol on maximally tolerated oral therapy and a PCSK9 agent. That's about, you know, 10% of all patients who need cholesterol lowering. So it's a pretty large market of patients who require additional lowering of cholesterol after oral and PCSK9. Then the second group is, which you mentioned, homozygous FH, HoFH. So these are patients who have a mutation, two mutations in the LDL receptor. They have LDLs of a thousand, six hundred, seven hundred, very high levels from birth, heart attack, you know, teens, so it's a very severe rare disease. It's an orphan disease, about three thousand people, and the ANGPTL3 mechanism is particularly effective in those patients. So it's a rare orphan disease and also this much larger group of refractory hypercholesterolemia. Those are the two indications for ANGPTL3. Right. Understood. And one of the things I wanted to discuss was, you know, some of the implications of the fact that HoFH is an orphan disease with such a small patient population. I guess, what does that mean for the clinical development of VERVE-201? Yeah, I think it opens up the possibility of a much quicker path to registration. The monoclonal antibody targeting ANGPTL3, called Evinacumab, was approved based on a study of, you know, 50-60 patients, pivotal study. So it gives us a potential path to take the standard rare disease kind of paradigm for approval. All right. So, just to be clear again, so is the intention the first patient population you'll begin a clinical study is HoFH before you expand to some of the broader populations? The initial phase 1 is actually likely to be in refractory hypercholesterolemia patients. Oh, okay. To get the dose, dose escalation done. All right. Glad I asked a clarifying question there. Great, so we only have about a couple minutes left here. I also wanted to talk about the partnership with Eli Lilly for Lp(a). I know this is a much earlier stage program than your other two programs, so I was hoping you could talk a little bit about the partnership and the target here. Yeah, this is this partnership is set up as more of a standard pharma-biotech collaboration, where we're doing the research, they're paying for all of it now. And then at the end of phase 1, the program transfers over to them, and then we have the ability to leave it as a royalties milestones or opt in for a profit share. And this is a super exciting target and kind of reflects, I think, our philosophy as well as Lilly's philosophy of a compelling target, multiple treatment options, you know? There's a pill that Lilly has developed against this target. There's also an siRNA that Lilly has in development right now, and then on top of that, they're interested in a gene editing approach as well. So take a compelling target, have multiple options. The cardiovascular space is so large that some fraction of patients will choose one of these, and there's... You know, have an option for each patient, essentially. Okay. Got it. Yeah, so, easy question for last question. So if you could just talk about the balance sheet and cash runway, and also just maybe tell investors what we're expected to see before the cash runway is- Yeah. So our cash position at the end of last quarter was $575 million. It's a runway to late 2026. Within this budget envelope, we are expecting phase 1 data for 102, initiation of the phase 2 for 102. This is the PCSK9 program. And then for the ANGPTL3 program, we're initiating the phase 1 trial, and we should have phase 1 data for that program as well within this budget envelope. All right. Great. Well, I think that about wraps it up. Thank you so much for the time, Sek. It's been wonderful, and really looking forward to seeing those data in the first half of next year. Thank you very much for hosting us, Rick.