Can you hear me? Okay. Good afternoon, everyone. Welcome to 2024 Jefferies Global Healthcare Conference, last day. My name is Roger Song, one of the senior analysts covering mid-cap biotech in the U.S. It's my pleasure to have the fireside chat with Verve Therapeutics CEO, Sek. Welcome, Sek. Thank you so much. Great to be here, Roger. Awesome. All right, so we believe we have a lot to cover today and then in the next 25 minutes. But before that, do you have any intro remarks for the folks who may not necessarily be too familiar with Verve? And then we can go into the Q&A. Yeah, I'll keep this short. Basically, Verve Therapeutics is developing once-and-done gene-editing medicines to treat heart disease, specifically heart attack. Think one-time treatment, permanent lowering of LDL cholesterol. We often get asked, do you really need this kind of therapy, basically a one-time gene-editing treatment to lower cholesterol? Because there are other options in the marketplace right now to lower cholesterol. The unmet need really here has to do with the name of the game for cholesterol lowering and prevention and treatment of heart attack is not only how low you take the cholesterol, but how long? The challenge, the problem with the current model of daily pills, intermittent injections, is that nobody's basically doing it. Instead of effective lowering for a long time, you're basically getting just transient lowering for a few months, maybe. What we hope to do is address that problem with a one-time therapy that would lead to dramatic, but more importantly, durable lowering over decades. Yeah, you know, given this is a chronic disease, one-time treatment can have a durable effect. Absolutely makes sense. Nothing is easy, right? So we're going to go into the development status of your 101 and 102. But it's the dream if you can get one-time treatment for the cholesterol lowering effect. So, okay, so your gene therapy, gene-editing therapy. And then this is a novel modality, understand, probably take multiple iterations to get there and then to be really for the become a real drug. So tell us what happened recently for your 1st generation 101. How should investors interpret the data in terms of the safety and the PK/PD and the efficacy? Yeah, so our pipeline involves three major axes of risk in terms of lipoproteins, lipids. One is the LDL axis, another is the triglyceride and LDL axis. The third is Lipoprotein(a). And we have a product against each one. Each of our products has a very similar configuration of an editor and a guide. The guide tells the editor where to go in the genome to make the edit. Those two nucleic acids are packaged in a lipid nanoparticle. For the PCSK9 program, we have two product candidates that differ only in the delivery system. The guide and the editor are the same. We call it VERVE-101 and VERVE-102. VERVE-101 is what we took to patients first. And we presented data last year and a little bit earlier this year on about 13 patients. And what we showed was the whole system can work. The editor and guide led to turning off the PCSK9 gene in the liver of patients. We got up to a 73% reduction in LDL in patients and durable out to 9+ months after a single treatment. Really very good proof of concept that the editor and guide are working as designed. But at potentially therapeutic doses, we had safety, transient laboratory abnormalities around the time of the infusion of the lipid nanoparticle. We believe these transient reversible laboratory changes, both in ALT and in platelets, are due to the lipid nanoparticle delivery system. That's what's been switched out basically for the 102 product, the 2nd-gen product. The 2nd-gen product uses the same editor and the guide as 101, but the delivery system is entirely different, which we'll talk about. We believe that that delivery system change is going to address those transient laboratory abnormalities that we saw. Yeah, yeah, let's drill down this because we want to understand a little bit more detail around what's the difference between 101 and 102 in terms of the lipid nanoparticle delivery system. And the difference is number one. Number two, why this difference actually will drive the difference in the safety profile you have been seeing. Yeah, so before I drill into the mechanism of action, just want to tell you about the product itself again. So we have a base editor. So you have different editing approaches. We prioritize an approach that makes a single spelling change in the DNA rather than cutting the DNA, which is what standard CRISPR-Cas9 does. And our single spelling change is intended to happen in the PCSK9 gene. And that change, an A, letter A is changed to a G at one spot, basically turns off the gene. The editor and the guide, as I said, are packaged in this lipid nanoparticle. The drug is delivered as a one-time intravenous infusion over a few hours. And once infused into the bloodstream, the lipid nanoparticle is actively taken up by the liver, hepatocytes. And then ultimately, as I said, the DNA spelling change is made. Now, the lipid nanoparticles in general are composed of four components, what's called an ionizable lipid, a PEG lipid, phospholipid, and cholesterol. The phospholipid and cholesterol are pretty generic to all lipid nanoparticles. But the ionizable lipid, and particularly the ionizable lipid, is the key component that determines the efficacy and the safety, the potency and the safety. The ionizable lipid that we used in VERVE- 101 was in-licensed from a company called Acuitas Therapeutics. And we are the first to take that ionizable lipid and that LNP construct to patients. And it had the profile that I described of good efficacy. But at efficacious doses, we saw these lab abnormalities. For 102, the 2nd-gen product, the differences are that the ionizable lipid is different. And in this case, it's licensed in from Novartis. And then the second difference is that we've added a targeting ligand called GalNAc, so a fifth component to the ionizable lipid. And that GalNAc allows the lipid nanoparticle to enter in through the GalNAc receptor on the surface of liver cells called ASGPR. So those are the two principal differences. The ionizable lipid is different, and we've added GalNAc to 102. These two changes, we feel, will address the transient laboratory abnormalities that we saw because, number one, in our own preclinical data, when we look at 101 versus 102, with 102, we do not see these laboratory changes in preclinical models at therapeutic doses. And second, the ionizable lipid component, which is being used in 102 that we've licensed in from Novartis, has already been tested in third-party clinical trials with over 100 patients. In those trials, the ionizable lipid has been well tolerated and has been efficacious. Both the preclinical data and the prior human experience gives us a fair amount of confidence that 102 will address the laboratory issues that we saw with 101. Got it. Yeah, I think that's a confidence. And then in your, I know the Novartis, this license to another company, they have done almost like 100-patient kind of clinical data, which have not seen significant change for the liver enzyme stuff and what you've seen for your 101. For your internal, how much you have done, because that's something we haven't seen. Number one, have you done head-to-head compare 101 and 102? Two, when maybe investors or the public will see some of the data from you, is that necessary to release such data? Yeah, I mean, we've done a fair amount of work on both 101 and 102. And almost all the data that we generated for 101, we did, it's in the public domain. We had a paper in Nature a couple of years ago that described the product and so forth. And then for 102, we've disclosed some of the data. And more generally, we've characterized it as that the preclinical data look very much like, let's say, the experience from Intellia in terms of their product, where they use the same ionizable lipid. And I think that, so as a result, as I said earlier, we're quite confident that this will address the issues that we saw with 101. Got it. Okay, good. All right, so now you are moving forward with your 102, and then it's into the clinic. So what will be the next data update from there? And understanding this is the partner with Lilly, then they will have the opt-in option there. And then how should we think about the opt-in package in 2025? That's probably the guidance. And then how much data will be generated before you deliver the opt-in package to Lilly? Yeah, this gives me a chance to talk about the patient population we're studying and the study design. So this study is called HEART-2. It involves patients with heterozygous familial hypercholesterolemia, abbreviated HeFH. It's a genetic form of high cholesterol, about three million patients in the U.S. and Europe. It also includes a group of patients called premature coronary artery disease. These are patients who have had a heart attack at a young age, men less than or equal to 50 years old, women less than or equal to 60 years old. This is about 20% of all heart attacks. It's a pretty sizable population. These are the two groups that are being studied. And you might ask, why are these people being studied in this trial? These are two groups that I think would get a differentiated benefit from our therapy, where the value proposition is not only how low, but for a long time. So these two groups of patients need decades of LDL lowering, and that's really what we hope to offer. So those are the two patient populations being studied. It's a single ascending dose design, roughly four dose levels, and then 3-9 patients at each dose level. And we're hoping to complete the dose escalation to get to an effective dose and one that's tolerated. And so what we hope to, what we plan to release next year is that dose escalation. And the key goal there, of course, is to be able to select one or maybe even a couple of doses to take forward to phase two. So that's really the principal goal here, safe and effective doses to take forward to a larger number of patients in a phase two. And then in terms of what the Lilly relationship that you mentioned, just to kind of clarify what that is, right now Lilly has the option for minority product rights on the PCSK9 program. What I mean by that is that at the end of phase one, we'll be able to show them this dose escalation data, and then they can decide to opt- in. If they do opt- in, then they pay for a third of worldwide subsequent development costs. In return, they'll get 50% of US profits. The other 50% of U.S. is Verve, and then 100% of ex-U.S. is Verve. So that's why we characterize it as minority product rights. Importantly, Verve has control of development. In addition, Verve Books revenues. This is the relationship right now. What we would hope to show to Lilly at the end of phase one would be that dose escalation data and then the go forward doses for phase two and a development plan. On that basis, I think they would be making their decision on opt-in. Okay, and then the timeline is sometime in 2025 to give the data update and then deliver the package to Lilly. That's right. And then in terms of the expectation for the opt-in package or the upcoming data readout, now we have the benchmark from the 101, right? So you see very robust PCSK9 reduction, LDL-C reduction, some kind of a safety, overall safety profile. So if you keep this efficacy, LDL and the PCSK9, and then dial out the liver or the thrombocytosis kind of a safety signal, will that be considered as a very successful opt-in package to Lilly? We believe so, yeah. I think that the goal here would be to have LDL lowering in the range that we got with 101. We certainly like the efficacy we saw and then dial out the acute LNP-mediated safety. The durability we expect to be there as well. We've already seen with 101 with base editing durability out to 9+ months after the one-time treatment. So in terms of people often ask, what's the benchmark for LDL lowering? I think there the benchmark would be something like Inclisiran, the siRNA that is marketed right now by Novartis. They essentially have seen kind of two different numbers, I guess, in terms of the based on the patient population, in terms of degree of LDL lowering. In HeFH patients, compared to baseline, the degree of LDL lowering is roughly 40%. In ASCVD patients, not HeFH, the degree of LDL lowering compared to baseline is roughly 50%. We'd like to kind of, of course, get as high as possible, but those are two, I think, appropriate benchmarks. The differentiating factor for us, of course, is after the therapy, instead of having LDL lowering for a few weeks or even a couple of months, a few months, ours would be durable for the life of the patient. Got it, got it. And then so you have some data from the 101, and then you are doing the phase, the 102, and then for Lilly to make the decision, how much Lilly will consider the 101 to make the decision on your 102? And also understanding you are doing some additional analysis on the 101, how much learning you will apply to 102 and/or impact this development on the 102? Yeah, absolutely. The risk from 101 and 102 in terms of the development and the Lilly decision. Yeah, our explicit goal over the last couple of years is to have a couple of different product candidates for PCSK9 and have them both evaluate in the clinic and pick basically one of the two to take forward into a phase two. That's what's playing out right now. We chose to have two product candidates for PCSK9 because it's an incredibly compelling target. On top of that, we knew that delivery remained a key risk. So we wanted to address that risk by having two different delivery formulations for the same editor and guide. Now, I think we have information on 101, its initial properties. We paused that trial to evaluate whether there could be ways we can mitigate the laboratory abnormalities. Meanwhile, we started the 102 trial. As I said, we're expecting to complete that enrollment next year and have the data readout. I think Lilly, as we and Lilly, will be looking at both data sets and saying, all right, which of the two is ready to take forward into phase two. Now, in terms of 101 and the investigation we're doing to understand the abnormalities, the mechanism, but more importantly, might there be mitigation measures? I think those are important for 101, but also what they might allow us or think about even for 102. And one of the ways you could imagine addressing the 101 issue is what's called split dosing. So you could imagine that instead of giving the full dose, where we did see efficacy, but we saw some safety signals, maybe you cut that dose in half and basically give it twice, day one, and then maybe 30 days later, the second dose. We've seen in non-human primates, some initial pilot non-human primate studies, that that kind of approach can actually lead to stacking of editing and efficacy without compromising any safety, without adding to any safety issues. That might be a very reason, and those are the kind of things we're thinking about now in the context of investigating 101. Got it. Yeah, it's still going to be one-time treatment. Hopefully, the efficacy is durable, but the dosing kind of regimen can be slightly different. Given it's LNP, not AAV, you can re-dose. Exactly. [crosstalk] This would be what we call single course therapy [crosstalk]. Two doses split by a very short period of time. Yeah, got it. Okay, and then move forward into you have the dose escalation data, deliver to Lilly, make decision, and then you move into the next stage. What would be the next clinical trial kind of design look like, expansion versus the registrational pass? Yeah, so phase two typically will be to find the go forward dose for phase three, of course. And typically in the past, there's been a couple of different doses explored in a phase two to make sure that all the patients are getting appropriate reduction in PCSK9 and LDL. And that's what we envision, a randomized control phase two with a control group, of course. Then phase three, the registrational trials, in this space, thankfully, there's a fair amount of precedent. And I think the most recent precedent is siRNA against cholesterol. And if you recall, just a few years ago, siRNA was a brand new treatment modality that had a fair number of, fair amount of conversation about efficacy and safety, and this is a genetic medicine for cholesterol and so forth. Even with all that, the FDA precedent has been for FH, the registration trial, or called Orion 9, conducted by Novartis and the Medicines Company, was 500 people. So that gives us a benchmark of what we might be expecting. The registration was done based on LDL cholesterol. That's what our base case is right now. Got it. Okay, good. And then the PCSK9 is active. We already have approved the monoclonal antibody. We also have siRNA. Also, we have the oral kind of a drug upcoming. So how do you think this one-time treatment gene editing therapy is going to fit into the future treatment landscape? What is the initial kind of targeted population? What will be the ultimate ambitious goal for the treatment for the patient population? Yeah, I mean, I can't emphasize enough that the challenge right now is not the lack of availability of options to lower cholesterol, but the challenge is really time on treatment. And patients just are not on these medicines for very long, and therefore they're not deriving any benefit, even though they theoretically could. So we foresee a future where there are multiple options for cholesterol lowering, a daily pill, twice a month injection, twice a year injection, and a one and done. And we think an important fraction of patients will choose the one and done approach. And some recent surveys bear that out. There was a recent survey done of several thousand people who had high cholesterol or a prior heart attack. They required lifelong LDL lowering. They were given these four options. And about 40% of people said they would prefer a daily pill. About 14% said they would prefer a twice-a-year injection, 4% said twice a month. And then a third of people said they would prefer a one-and-done. So there's, I think, going to be a good amount of appetite for this kind of approach. The other point to make is this class, PCSK9 therapies, there's two antibodies, twice a month injections, one siRNA, twice a year injection. Those three medicines right now, this year, are expected to sell about $3.6 billion annualized based on first quarter numbers. So what's remarkable is that $3.6 billion represents only about 2% of eligible patients. So it's a very large market opportunity because you're already seeing a good amount of sales for a very small fraction of eligible patients. And so what we'd like to do is, of course, potentially eat into that 2% that are using it now. What about the other 98% of people who are eligible for these therapies that are not taking them? We think a lot of those would actually prefer a one and done. We think a lot of them are not on these medicines because of the chronic care model, the requirement that they take a daily pill for their whole life. Yeah, that's a very big number difference. And I understand not going to be everyone going to right away to take a 102 or your PCSK9 gene editing, but you will find people willing to do that. And then once you have more patient experience, safety and efficacy, people will say, okay, that's one of very viable options out there. That's right. I think the number of people that are potentially eligible for these kinds of medicines is huge. We're starting with a genetic subset of the disease. These are patients who have sky-high cholesterol from birth based on a DNA mutation, typically. Those are patients who would be particularly motivated, I think, to take on this kind of therapy as early adopters because their cholesterol is not high because of their diet or lifestyle, but because of inheritance. The prospect of a curative, functional cure for their high cholesterol with a one and done, I think, would be particularly attractive to them. That's about a couple of million people in the U.S. and Europe. Then you could expand from there to anybody who's had a heart attack, which is about 50 million people in the U.S. and Europe. A couple of million people, [audio distortion] will take it first. For investors, m aybe lastly, I mean, I think investors probably underappreciate how big the platform or the research team you have. I think we talked with you the last time, the CSO kind of changed. So tell us about your platform, understanding your license from Beam Therapeutics for the gene editing therapy, the technology, but also you have your internal gene editing team. So tell us a little bit more, spend a minute. Yeah, I mean, I think that this year is all about de-risking the delivery system. But once that's de-risked, it's very modular in terms of the cargo that you can put in. Our first program is PCSK9. Our second one is ANGPTL3 for cholesterol as well. The third one is Lipoprotein(a), a very hot target, a highly genetically driven target that could be cured with our therapy. And so that's using an editing approach other than base editing. We have not provided public guidance on exactly what that approach is, but that's internally developed. Then we have another target that's also cardiovascular, that's liver-based, not disclosed yet, but that's super exciting as well. And then of the five programs we have, only one of them is non-cardiovascular. And this is a liver disease that we're working on a partnership with Vertex. So we have a very robust pipeline, a very modular set of cargo that can be switched out once the delivery system is de-risked. But the focus is largely on cardiovascular disease. Awesome. Great. Thank you, Sek, for attending, and thank you, everyone, for listening.