Jefferies 2024 London Healthcare Conference. My name is Roger Song, one of the senior heads covering biotech in the US. It's my pleasure to have the fireside chat with our next company, Verve Therapeutics. Welcome, Sek. Thank you so much, Roger, for hosting us. Awesome. Yeah, maybe, Sek, if you can give us a little bit of an overview of the company in a couple of minutes, and then we can go to the conversation. Yeah, so Verve Therapeutics is trying to solve heart attack, the leading cause of death in the world. And a key answer to heart attack has been known over the last several decades, which is to get cholesterol, blood cholesterol, as low as possible for as long as possible. And by low, I mean like one millimole or 40 milligrams per deciliter. Now, we have a bunch of options right now to be able to lower blood cholesterol to treat heart attack. Despite that, the majority of patients are actually not getting their LDL levels very low. In fact, about half of all patients who start on a cardiovascular medication are no longer on them within about 6 months or after initiation. So what we'd like to do is kind of change the current paradigm of care, which is daily pills, intermittent injections to lower cholesterol, to really a one-and-done. One-time therapy, lifelong lowering of cholesterol. That's really the vision for the company. We started in 2018 with a set of targets that, when turned off in the liver, genes when turned off would lower cholesterol lifelong. We've developed a series of gene-editing medicines with the property of, again, a one-time intravenous infusion. The medicine will turn off a given gene in the liver, for example, PCSK9, and the result is lifelong cholesterol lowering. We got the approach to work in cells, mice, non-human primates, and then started treating patients in 2021. Now we have solid human proof of concept that this whole approach can work in patients. We're iterating on the delivery system. With our current product, Verve-102, we expect data, human data in the phase one in the first half of next year. That's a key milestone for us. In addition to the first product targeting PCSK9, we have several more, one targeting ANGPTL3, another targeting Lp(a). Again, all the same idea, one-time intravenous infusion leading to lifelong lowering of cholesterol. Excellent. Yeah, I think the whole approach makes a lot of the clinical sense because one-and-done, holy grail, to lower the cholesterol, the risk factor lifelong, right? So versus the other modality, we have a lot of other modalities, but the compliance is always the issue. We know if you're not continuously reducing the LDL-C, you're not going to get the benefit, long-term benefit. So maybe we can focus the effort today, focus on your lead program, 102, given you're in the phase one and you're going to have some very meaningful data results next year, early next year. So maybe give us an update where the trial right now. I think you're dosing, you already dosed the seven patients in two-dose cohort. What have you been seeing at a high level? I know you haven't really given us the detailed data, but what have you seen and what you have communicated to the street? Yeah, so maybe I can start with just explaining the medicine. It's a base editor, adenine base editor. This is really designed to make a single spelling change in one spot in the DNA sequence. And for us, it's in the PCSK9 gene. And the intended consequence is to turn off the gene. And then the blood PCSK9 level would come down and blood cholesterol will come down in turn. So that mRNA for the editor and then there's a guide RNA, those two components are packaged in the delivery system, a GalNAc lipid nanoparticle delivery system that we have developed internally. And with this product, we've dosed seven patients, as you said, across two dose levels, 0.3 mg/kg and 0.45 mg/kg. And so far, the medicine has been well tolerated across these seven patients. And we're dose escalating to the next dose level. In the first half of next year, as I said earlier, we should have data across multiple cohorts with this product. That's the H2 of next year. In the second half of next year, I think we'll have the full dose escalation completed. We have an important partner in Eli Lilly who will be making a decision based on that phase one data in terms of opting into the program and helping us with development going forward. That decision will be in the second half. Really important year for us with a milestone in the first half and also another important milestone in the second half of next year. Excellent. It's a good sign you can dose two dose cohort without seeing a safety signal there. That's good. And then so how many dose cohorts you plan to do and then how flexible you can advance and escalate the dose cohort? And then what's the benchmark we should see there? Yeah, the base case is we've designed it to be about four cohorts, minimum three patients in each cohort, but we can extend up to nine. So it's a flexible study design, adapted to study design. And I think in the H1 of next year, as I said, we'll be providing the initial data. In January, we'll be able to clarify some more details on the exact, more exact timing on the volume of data, the degree of follow-up in January. Got it. You're going to give us a little bit more guidance in terms of what to expect for the first half of next year, this data readouts. And then so what's out there, right? So when you give us the guidance, and then what should we look at compared to 102 in terms of the LDL reduction? And then also what will be considered as a good kind of outcome just using without the detailed guidance, but using the current landscape to give us some initial kind of context there? Yeah, there's a range of different agents out there to lower cholesterol. If you take an example, one of them is an siRNA that's injected twice a year called Inclisiran. That agent, and if you look at the phase three trials for that agent, the degree of LDL reduction varies by patient population. And there are two patient populations that have been studied and are also being studied in our phase one trial. One of them is a genetic disease called heterozygous familial hypercholesterolemia. This is a very serious morbid disease characterized by sky-high cholesterol from birth based on inheritance. It leads to premature heart attack. Often the first presenting symptom is death, fatal at a young age. This disease affects roughly three million people in the U.S. and Europe, so a very common genetic disease. In that patient population, HeFH, Inclisiran lowers LDL by about 40% compared to baseline. There's another group called atherosclerotic cardiovascular disease. This is basically a garden variety heart attack patient. That patient population is about 10% of the US. That's a very large prevalence. That group, Inclisiran lowers LDL by about 50%. So I think that's kind of the range that we would be thinking about for our target product profile. Of course, the key difference for us is whether it may be 50% LDL lowering, but it's going to be instead of a few months for us; it's really lifelong. Even it's like twice a year, not necessarily every patient will comply with that. So that's why with this one-and-done therapy, you can get to the level, maybe comparable level, but you still enjoy the whole life kind of. Yeah, because this is really a problem of cumulative exposure to cholesterol. Think about it as kind of area under the curve, and so you want to lower LDL by a certain amount, but you want to do it as long as possible, so it's really that area under the curve is really important, and I think we're really designed to be able to minimize that exposure over a lifetime with our approach. And then, in terms of you decide when to announce the data for the interim data, so what will be the key consideration? Understanding maybe you need to take a look at the initial safety profile because a lot of the safety signal happening in the early stage of the treatment. And then so the efficacy side, LDL reduction, it takes not too long to get to the level. And then obviously you're not going to get a full durability, but when you will start to say, okay, I can release the data, make the decision. Yeah, on the efficacy side, the LDL drops within about a few weeks. So by 28 days actually after this approach, after this DNA gene editing, 28 days after treatment, you're getting to the nadir of the LDL. So you can get a pretty good feel for the effect of the medicine in a very short time frame. I think we would hope to release data when we have a sufficient sample size where we're comfortable with the people who are going to be comfortable with the safety profile, the acute safety profile. And then second is I think we'd want to achieve a target product profile and an efficacy level of the type that we're talking about, 40% for HeFH patients, 50% or more for ASCVD patients. And I think we'll put out the initial data set once we're able to clear both those ideas. Is that fair to say you can say for sure, you need to see it's no safety signal, but in terms of the efficacy side, you can keep those escalations until you see the target profile without hitting the safety, and that's a flexibility you may have. Yeah, and that's the whole goal, right, to get to the right TPP without having any adverse effects for any dose escalation. So I think that's a good summary. Good. And then, next step, you have a Lilly partnership, and then they may have an opt-in option, although you still control the full kind of development and commercialization. So tell us when and then how Lilly is going to make that decision, and then what kind of a data package they need to make the decision. Yeah, so the relationship is structured as they have the ability to opt into the program at the end of phase one. So the last patient dosed in the phase one. After that, we have some time to put together a data package, give it to them. They have some time to review that data package and then make a decision as to opt in. When they opt in, they're responsible for a third of worldwide development costs from that point onward. In return, they would get 50% of US profits. The other 50% of US profits is Verve's, and then 100% ex-US is Verve's. So I think one way to characterize the economic rights is that we have majority economic rights, they have minority economic rights. And then importantly, we have control of development and we book revenues. And so if you, as you know, this is a set of rights that we had given to Beam Therapeutics when we started the company and when we got exclusive access to the base editing technology for these targets. And then last year, Lilly purchased those rights from Beam and really stepped into Beam's shoes. And so now Lilly is our partner and has the potential to opt in next year. We expected this whole process to play out in the H2 of next year. So again, the first half of next year is an initial data release. The H2 would be probably the Lilly opt-in. And then how did that play into the second half final data from your phase 1? I think the final data will likely be concurrent with the Lilly opt-in decision because that's probably what they would be looking at. And then so maybe the next step after the phase one and then you're going to move into the phase two. Yeah, so we're basically guiding to initiation of the phase 2 in the second half of next year as well for this product, VERVE-102. And then we have another pipeline product, ANGPTL3, that we just dosed our first patient. And so it's very exciting to have two products in the clinic already for this approach. And the VERVE-201 targeting ANGPTL3 is actually going to be continuing to enroll all of 2025 as well. Yeah, we're going to spend a couple of minutes on the 201 as well. So back to the 102 and then how should we think about the initial kind of maybe low hanging fruit of the patient population you can address if you can get to the approval? And then what will be the aspirational goal for the whole kind of approach? Yeah, so the clinical development path, of course, right now we're in a dose escalation phase to identify a dose for Verve 102 targeting PCSK9. The phase two will be to probably explore a couple of the doses in a larger number of patients and then to select the phase three dose. And the phase three, I think an initial phase three would likely involve that genetic subset of patients, heterozygous FH. That's a good group to start with, again, because it's a genetic disease and we'd be offering a functional genetic cure for those patients. It's actually, as I said, about three million patients in the US and Europe, about 20 million patients worldwide. So it's a relatively common genetic disease. And then the approvals to date for any LDL lowering medicine in this patient population has been based on just LDL cholesterol alone. There has been never a clinical cardiovascular outcome trial that's been required or completed in the HEFH patient population, so this gives us, I think, a more straightforward path to registration, hopefully based on LDL, and that would be the first study, and then we likely would go forward with another study focused on the garden variety heart attack patient, the atherosclerotic cardiovascular disease patient, and that, again, the approval can come likely based on just LDL in that group as well. Very good. And then, so you do have a first gen and a 101 in which you use a similar kind of maybe the same construct as the 102, but different delivery vehicle. So tell us what's the new finding from the 101 and then how this can translate into the 102, why you have confidence in the 102, that addresses all of that. And then you recently have some durability data from the 101. And then how should we interpret that data to the 102? Yeah, so we had simultaneous development of two products for the PCSK9 target, Verve-101 and Verve-102. What we've been talking about just now is 102. And we're going to have data in the first half of next year for 102. But we've also completed a 101 study. And the difference between the two products is same cargo, same editor, same guide in both products, but they differed in the delivery system, the lipid nanoparticle delivery system. The reason we decided to more or less simultaneously evaluate two products in the clinic is because we knew that liver delivery of mRNA was still a major risk when we started the company. And we wanted to have essentially a couple of shots on goal with respect to delivery. Now, what we learned from that Heart-1 study of Verve-101, which we dosed about 13 patients, we learned human proof of concept. This whole approach is going to work, is working, and we were able to, in some patients, basically get a very dramatic lowering of blood cholesterol after the one-time treatment, up to 60% LDL lowering, and then that LDL lowering has been durable 18 months plus after the initial dosing, so a one-time therapy, LDL comes down 60%, 18 months later, it's still down 60%, so really very encouraging result for the approach, for the technology, again, human proof of concept for the first time showing that in vivo base editing can work. Now, with 101, we also did have some challenges with the acute infusion where we saw some laboratory abnormalities emerge, specifically a rise in the liver function test and, in one patient, lowering of the platelet count, and those two changes were transient, reversible, didn't lead to any clinical problems for the patients, but we decided to pause that trial in March of this past year with really two ideas. One is to better understand what was happening, and second, we knew that we had 102 really ready to go as well, and so for those reasons, 101 was paused. Now, what we've learned about 101 beyond the efficacy, durability, the proof of concept is that we've done some non-clinical studies with 101 and learned that basically the lipid nanoparticle, not the cargo, not the mRNA or the editor mRNA or guide, but rather the lipid nanoparticle is responsible for the laboratory abnormalities that we saw. And as you know, that's what's been switched out, going to 102 from 101. And we have confidence that the 102 will avoid those laboratory abnormalities based on three reasons. One is the specific ionizable lipid that we're using, and we can talk about that in a minute. The second is that this ionizable lipid that we're using has been tested by another company in over 100 patients, and it's been well tolerated. And lastly, we've already treated, as I said, seven patients, and we have a good safety profile so far. This ionizable lipid we've licensed in from Novartis and really has a very good profile in preclinical studies and is emerging in our own hands with a good profile in clinical studies as well. So we feel that 102 will retain the efficacy and durability we saw with 101, but avoid the laboratory safety abnormalities that we saw. Yeah, that's a goal, right? So you do the iteration from two assets and then the second one potentially can improve upon the. First one. Yeah, yeah, from the first one. And then you just recently announced some durability data from the 101. I understand one patient is up to 18 months at a high dose. And then I think the mid high dose 0.45 for you, it's too early because you have multiple patients. So when, if at all, you will plan to announce the durability data from those patients? Yeah, all the patients are being followed ongoing, and I think we'll be able to update on the durability at periodic intervals going forward. But I think this really looks fundamentally different from viral vector gene therapy. So in vivo gene editing, so where you're editing the endogenous DNA, looks like it truly is going to be durable for a long time. And the biologic reason is that the liver does regenerate every 6 to 9 months in primates. But the source of the liver regeneration is actually mature hepatocytes. And when we come in initially and edit, base edit, we are editing essentially almost all hepatocytes. And so when they divide to give forward to new hepatocytes, they're carrying forward the DNA edit. And that's the reason for this durability. We've seen the durability out to 18 months now in patients with our own medicine. Intellia, a company doing in vivo liver gene editing for TTR, just published over the weekend data over two years now after their form of DNA editing in the liver. And then in non-human primates, there's data out to 7 or 8 years after a one-time therapy, specifically for the PCSK9 target gene editing. So there's really good evidence that this is going to be durable for a long time after the one-time therapy. Excellent. That's great. We're going to continue to get some validation from your 101, but you'll keep pushing the 102 and then see the safety if that's something can be addressed, and by the way, the safety signal typically happened in the acute phase. Yeah, so all the laboratory abnormalities occurred within the first couple of days after infusion and resolved within a few days after infusion. So all the safety issues were acutely after the treatment. And so the fact that we haven't seen that in the first seven patients that we've dosed is encouraging, and then we'll continue to dose escalate. Basically, next year for the initial data, when you give us the full dose cohort, we're going to. We'll have a minimum of 28 days follow-up in each patient. Got it. Okay. So, last a couple of minutes, I know you want to talk about the 201 and then maybe other earlier pipeline with the partnership. So where you are with the 201 and then when we're going to start to see data, and then also how they're going to play with your 101 given they're all targeting similar? Yeah. So basically, if you think about cholesterol, the way our pipeline is set up is cholesterol in the blood is carried in three different particles. One is LDL. The second is what are called triglyceride-rich lipoproteins. The third is Lipoprotein(a). So we have a product, a target that addresses each of these. PCSK9 addresses LDL. ANGPTL3 addresses LDL and triglyceride-rich lipoproteins. ANGPTL3, when you turn it off, the blood LDL comes down, the blood triglyceride-rich lipoproteins come down. And so our second product, Verve 201, targets that gene. It's in a phase one right now. We just dosed our first patient. We're going to be enrolling all next year. And the development path here is what's the right patient for this drug? The right patient for this drug is patients who already have on a statin and a PCSK9 mechanism, and the cholesterol is still too high. These are patients called refractory hypercholesterolemia, and it's about 10% of all patients with ASCVD. It's a very large group of patients. For those patients, it's already been shown by a monoclonal antibody targeting ANGPTL3 that if you give the ANGPTL3 mechanism to those patients, the LDL will come down an additional 50% on top of statin plus the PCSK9. That's really the intended patient population for the ANGPTL3 product. There's one other group, a genetic group called homozygous FH, a rare orphan disease. Those are really the two groups for Verve 201 targeting ANGPTL3. We're going to start to see some data from you. So the data, I think we're enrolling next year. I think we'll probably get data toward the end of next year or early into 2026. Very good. And then, outside of those two, given you have a pretty broad kind of gene editing platform, and then what the other pipeline, Lp(a). Yeah, the third product is Lp(a), a very hot target right now. And so Eli Lilly, for example, over the weekend, again, at the American Heart Association meeting, described data for an oral agent targeting Lp(a). They also have an siRNA targeting Lp(a) in a phase three. The oral agent was phase two data. And then they're working with us on this Lp(a) gene editing approach. And I think one of the key things about next year for us is that once we de-risk the delivery system with Verve 102, that GalNAc LNP that we're using to deliver editors, that GalNAc LNP is the same delivery system being used in Verve 201 as well as the Lp(a) program. So this 102 result will unlock the rest of the pipeline as well from a delivery perspective. And then the cargo, the editor for the first two products is the base editor. For the Lp(a) product, it's actually an editor that we've developed internally that we've not provided public guidance on the exact details of the editor, but it's custom developed for the Lp(a) target. And so we're pretty excited to kind of take that forward. It's in preclinical right now. Cash position, then what's the runway? Last one. Our cash position, we have $540 million at the end of the last quarter. This takes us through 2026, so roughly 27 months or 26 months. We will be able to get through the phase one for 102, start executing on the phase two, and we'll also be able to get through the phase one for 201. Really a lot of important milestones next year. To summarize, really next year for 102, the key lead asset is really the first half is initial data, second half is final data for the phase one along with a Lilly opt-in decision.