Joining us for the next half hour. My name is Dae Gon Ha, one of the biotech analysts here at Stifel. And for the next half hour, we have the pleasure of having Verve Therapeutics. And representing Verve, we've got Dr. Sekar Kathiresan. So, Sek, I know it's been a busy period for you, but thanks very much for making the time. I guess we'll just level set. For those of us less familiar with Verve, can we just start off with your overview, Verve-102, and your general strategy on the pipeline front? Thanks, Dae Gon, for having us. Yeah, so Verve is focused on gene editing medicines for cardiovascular disease, so think one-time treatment, permanent lowering of blood cholesterol as a way to manage high cholesterol as well as treat heart attack. Our pipeline consists of several targets: PCSK9, ANGPTL3, and Lp(a). The medicine products in development all have the same kind of setup, which is editor, guide, package, and a lipid nanoparticle delivered as a one-time intravenous infusion designed to turn off a gene in the liver and lead to lifelong lowering of cholesterol. The products that are furthest along are for the PCSK9 target. We have two product candidates, Verve-101, Verve-102. Verve-102 is in the clinic right now, dosed about seven patients. We can talk about that across a couple of dose levels. Should have data for this, phase I data for this product in the first half of next year. VERVE- 201, which is our second program, second target in terms of ANGPTL3, we dosed our first patient there. It's really wonderful to have two molecules actively in the clinic. And then Lp(a) is preclinical, and it's coming along well. Yeah, so. OK, so another high-level question, probably as a repeat for a lot of people, but the Verve-101 and Verve-102, I know you presented this in one of the medical meetings earlier, but help us better appreciate what are the similarities and the differences between the two product candidates? Yeah, so they're both gene editing medicines, specifically base editing medicines. They share the same cargo, the same editor, same guide RNA targeting PCSK9 gene in the liver, but they're packaged in different lipid nanoparticles. The first one has a certain set of components, Verve-101. The second one, Verve-102, has a couple of different differences in terms of lipid nanoparticle. One is the ionizable lipid, second is the PEG lipid, and the third is the addition of a GalNAc targeting ligand. So these are the key differences. With 101, we started dosing patients in July of 2022. We dosed a total of 13 patients across several dose levels for the Heart-1 trial. And we had a lot of learnings. I think number one, the whole approach, in vivo base editing works. We were able to get high levels of editing in the liver, pretty dramatic reductions in blood PCSK9. The LDL came down up to 60%. Then over time, it's durable. In a couple of the patients, the LDL came down 60% at 28 days. Then a year and a half later, the LDL is still down 60%, really suggesting that this whole one-and-done concept is going to work. Now, at the same time, we had a couple of laboratory safety abnormalities appear after infusion of the lipid nanoparticle. This is a two-hour, two to three-hour infusion through the intravenous peripheral IV. A day or two after intravenous infusion, we had ALT elevations in a couple of patients and a platelet drop as well in one patient. We figured out with preclinical studies that all of that was due to, we think, the lipid nanoparticle itself, not the cargo. We were able to prove that using some nonclinical studies where we were able to administer a lipid nanoparticle where the editor was there, but then the guide RNA was non-targeting. It was scrambled guide RNA. This allowed us to isolate the problem we saw with 101 to the lipid nanoparticle. Now, what we've done with 102, of course, is switch out that lipid nanoparticle. We think 102, the current product in the clinic, is going to retain the efficacy and durability that we saw with 101, but avoid the laboratory safety abnormalities. That's really the data we'll be releasing in the first half of next year. OK, and then the nonclinical assessment, plus something that you and I discussed previously was preclinical experience with 101. So if we can maybe take a step back, like how high of a dose were you able to administer on the 101 safely? Or were you able to identify some of these same signals that you were seeing in, unfortunately, Heart-1 study? In patients for 101, the HART-1 trial, we did three dose levels: 0.1 mg/kg, 0.3 mg/kg, 0.45 mg/kg. Actually, we also did 0.6 on one patient, so four dose levels. And we had laboratory safety abnormalities appear at the 0.45 mg/kg level. For 102, the current product in trial, we just disclosed that we've dosed seven patients across two dose levels. For 102, we were able to start at 0.3 mg/kg and have cleared the 0.45 mg/kg and are in the process of dose escalating to the next dose level. Yeah, I think the update on that seven-patient was as of October, right? I guess two-part question is, are you able to maybe elaborate on what the split is between 0.3 and 0.45 for the seven patients? And what's been the longest follow-up so far to kind of get a better sense of what we saw in 101? Should we be expecting something in 102? If not, we can check that box off. Well, I think the safety abnormalities we saw in 101 all happened within the first few days. And we're well out beyond the first few days for all the seven patients. So we feel comfortable with the safety profile so far in the first seven patients across the two dose levels. It's a minimum of three patients at each dose level is where we design how we've designed the study. And then we can add more than three. And then, as I said, we're in the process of dose escalating to the next dose level. I see. If we go back to sort of the PK modeling, I mean, recognizing you're now dealing with two different compositions of LNP. One actually has a GalNAc on top of that, which should help, right? But is there any data for us to get a better sense of what kind of efficacy on the 102 should confer similar benefit as dose level 0.3 or 0.45 in Verve-101, if that makes sense? Yeah, I think leave aside 101, actually. I think for 102, I guess the question you're asking is, what's the dose range you're exploring, basically, in terms of efficacy and safety? Because I think the trial has four doses that you've basically set as part of the trial design, right? Right. But it's actually a flexible adaptive. There can be even many more dose levels if needed. But the base case is four dose levels, minimum three patients in each dose level. And I think the best guide there is really a lot of the efficacy or the potency, I should say, is determined by the ionizable lipid component. And so the ionizable lipid component that we're using in 102 is similar or is the same, actually, as what Intellia is using in its programs. And so the dose level, the dose ranges that Intellia has explored is probably a good base case for the dose levels that we're exploring in the Heart-2 trial. Got it. Then pretty soon, we're guiding to the first half of next year. You'll actually have our data across multiple dose cohorts. Right, so that's obviously a big question as we enter the new year. I think we all want to kind of turn the page on 2024 at this point. So on that point, I mean, first off, within the first half 2025, have you given any more color around whether this is going to be a standalone press release conference call or a medical meeting like you have done with the AHA presentation last year? And also, how much data should investors think about from coming out of that Heart-2 update? Yeah, these are the questions that are on most investors' mind right now after the most recent earnings release where we announced the seven patients. And it was well tolerated across the seven, across two dose levels. And what we're guiding to right now is that probably in the new year, around JPM time, we'll be able to give a bit more detail on the venue, the volume of data, the degree of follow-up in terms of these specific questions you're asking. Basically, more detail on that to come in January. Okay, and I guess one of the other kind of uncertainties when we think about upcoming data is that it's still somewhat small. So there is going to be variability. I think previously we talked about how LDL is more noisy versus a PCSK9. So is it still your stance that we should be paying more attention to the PCSK9 editing efficiency as well as its reduction? Or is LDL going to be something that we need to start focusing more on this time around? I think it's good to pay attention to both. I think it's one of the unique advantages of the targets we're going after. The PCSK9 is a direct readout of the gene that you're turning off. It's actually the protein made by the gene. It's thankfully secreted into the liver. So a direct measurement of that protein tells you basically how much of the gene you've turned off in the liver. And so but then the clinical readout, the clinical biomarker that is actually the approval endpoint is LDL. So you're going to measure that as well. So I think it's really nice to look at the both of them together. And there is an established relationship between the two when you get to lots of people. And so that's also known. And the degree to which any amount of LDL reduction translates into cardiovascular event risk reduction is also known. So there's kind of a very clean line you can draw across all of the results that we're going to see even as early as the phase I. OK, just to kind of check this box off, on the first Heart-1 trial, you had specific guidance from the FDA to go after severe and sick patients, which unfortunately manifested in some signals, adverse safety signals. What about this patient population? Are they more moderate or are they just as severe as the Heart-1 trial? Yeah, I think for the first trial, this was a brand new treatment modality. We were the first to probably take a base editor in vivo into patients, any company in the world, and so there was the sickest of the sick in some sense enrolled in the trial, and meanwhile, we have now some experience with the product. Others have experience with in vivo base editing as well or gene editing as well, and as a result, we've been able to move to less advanced, more moderate disease patients in this trial, in the Heart-2 trial, and one of the ways we're doing that is we are adding a screening test called a coronary CT angiogram, which is a non-invasive CT scan test that can look for heart artery blockages. It gives you nice pictures of the coronary arteries, the heart arteries. We're using that to basically exclude patients who have severe blockages already. OK, OK. Another interesting, I guess, nuance to Heart-2 or I guess Heart-2 is that you're going after heterozygous FH, but also premature coronary artery disease. Can you maybe walk us through why you decided to include the premature CAD patient population? And whether it's biologically or clinically, how should we think about their response degree versus a traditional HeFH, if you want to call it? Yeah, this gives me an opportunity to talk about the patient populations that we ultimately see our medicine adding unique value. Where in the white space or where in the overall treatment landscape do we see our product fitting in? Well, it's for patients who basically need LDL lowering for a long time, for decades. Who needs LDL lowering for decades? One is patients who have a genetic condition where they have sky-high LDL from birth. This is heterozygous familial hypercholesterolemia or HeFH. This disease is a serious morbid disease. About half the time, the first presenting symptom, much of the time, the first presenting symptom is death. They know they have high cholesterol. They have heart attacks at a young age. A lot of times, as I said, first presentation is fatal. And it's about a million people in the U.S. alone, about another couple of million in Europe, about 20 million people globally. So it's a fairly prevalent genetic disease. That's the group that we're going after, kind of offering "a functional cure" for their high cholesterol. The second group that needs lifelong LDL lowering is if you've had a heart attack at a young age. About 20% of all heart attacks happen in men less than 55, women less than 65. So if you're in your 40s and you happen to suffer a heart attack, you're looking at 30, 40 years of daily pills, intermittent injections, heavy treatment burden. And our value proposition is, well, let's replace that with a one-time therapy. So that's the reason these two groups have been chosen, HeFH and premature CAD. Now, the other question you asked was, is there a treatment response difference for the PCSK9 mechanism between these two groups? And the answer is yes. It's a small difference, but there is a difference. Roughly, the LDL lowering is about 10 points higher for the ASCVD patients compared to the HeFH patients. And the way you can think about that is just take an agent like inclisiran, the siRNA targeting PCSK9. They did a study in HeFH patients, phase III, called ORION- 9. And then Novartis and Medicines Company did a study in ASCVD patients, the premature CAD patients, a phase III called ORION- 10. And compared to baseline, in the HeFH patients, the LDL reduction with inclisiran was 40%. In HeFH patients, in CAD patients, the LDL reduction from baseline was 50%. So there is a little bit of a difference in efficacy between the two groups. OK, OK. And I know from the Heart-2 trial being small enough, stratifying probably doesn't make any sense. But is there any effort to make sure that the different dose cohorts have some semblance of matching attributes so that people, when they look at it, they can kind of take that into consideration? Yeah, I mean, I think each dose level will have a mix of either group, HeFH or premature CAD. It's small numbers, as you're saying. But I think we will probably have a better handle on the exact reductions in each of these strata as we expand to phase II. OK. So then when we take all these things into consideration, the patient population you're enrolling, the characteristic differences between Verve-101 and 102 on the LNP side, what's your sense right now in terms of efficacy, both on PCSK9 reduction and LDL reduction? It sounds like we should be expecting somewhat of a higher level of benefit in the 102 just purely based on premature CAD being included as part of the trial population. Is that the message we should be taking home? Or is it a little still too premature to jump in? I think this gives me a chance to talk about our target profile. What is it that we're looking to accomplish? If you think about LDL reduction, it's really there are two aspects that are super important. One is the degree of reduction, so 40%, 50%, 60%. The other is the kind of so-called the x-axis time, how long you can reduce for. What we'd like to do, our value proposition, again, is the time. Is a one-time treatment lifelong lowering? Because right now, what's happening is the average person that gets on a medicine is no longer on it 6 to 12 months after. The x-axis for them is not three decades or two decades, but it's six months. The degree of LDL reduction is not that great. Even though it's maybe 50% at the first month, at six months or seven months, it's 0%, no reduction, because they're not on it. And that would be different from us, right? So I think what we're looking to do, at least match what's out there on the degree of reduction. I don't think we need to be way better, because it's going to be reduced forever, the x-axis time. And it's all about cumulative exposure. The area under the curve, that's what's important. And our medicine is going to really control that area under the curve. So I think what we'd like to do, again, match inclisiran. So for HeFH, it's greater than 40% from baseline. And for ASCVD, it would be greater than 50% from baseline. I mean, in a way, Heart-1 has already kind of shown us that, didn't it? I think that's why I was saying in the beginning that we think 102 will match the efficacy and durability we saw with 101, but avoid the liver safety events. On that point, can you just quickly remind us, what was the latest durability data you presented on the Verve-101 front? Bearing in mind it's now paused, right, voluntarily paused. Yeah, so we're following those patients over time. So the patients that got treated last year, they're now 18 months plus out. The durability data that we showed was in one of the patients in the 0.6 mg/kg cohort. The LDL came down about 57% at 28 days after the one-time treatment. And then a year and a half later, the LDL is still down 57%. Now, this was a 29-year-old with HeFH who had a heart attack two years earlier, came into our trial at the age of 29, got our medicine one time, LDL came down 57%. And probably for the rest of that patient's life, it's going to be down. Yeah, fingers crossed. That's great. One of the other guidance that you've kind of set forth, even from last year, was since you have 101 and 102 as part of the PCSK9 umbrella program, you're going to look at both the Heart-1 and Heart-2 data before you decide which to proceed with. At this point, I mean, I'm kind of inclined to believe that 102 should go forward, given that 101 has had a little bit of a wrinkle on the safety front. So I mean, isn't it all kind of a foregone conclusion that 101 poses greater risk profile, therefore 102 should be better? What are you kind of waiting on still before you make that ultimate decision? I think what we'll do is we've guided to, in the first half of next year, having this data disclosure across multiple cohorts. And we're also guiding to a decision on the PCSK9, our announcement on the PCSK9 program. And what that will be likely is essentially identifying one of the two products and then a go-forward doses for phase II. We are guiding to phase II initiation in the second half of next year. And the way 25 is shaping up, Dae Gon, is first half is initial data from 102. Second half is likely the full dose escalation from 102, as well as the Lilly opt-in decision in the second half, and as well as the initiation of phase II, all for 102, all for the PCSK9 program. Gotcha. OK, OK. VERVE-201, you dosed the first patient. Is this something that we should be looking at? So the, I guess, anti-ANGPTL3 program from Regeneron as a bogey. I mean, you mentioned inclisiran. That, I think, given the mechanism, siRNA should be a better read-through. But here, this is a monoclonal antibody. So help us understand your approach versus how we should think about Regeneron's precedent. Yeah, I think that Regeneron, what it teaches us, the Evkeeza, which is a monoclonal antibody neutralizing ANGPTL3, teaches us how much LDL lowering you can get from near complete neutralization of circulating ANGPTL3. And that answer is about 45%-50% LDL lowering on top of PCSK9 mechanism. So it's a lot of LDL lowering you get in these hard-to-treat patients. And so we've seen that in our preclinical models. We created a monkey model of familial homozygous FH. And the LDL went way up in the monkeys. And then we came in with an anti-ANGPTL3 drug, our gene editor. And we're getting about a 47% LDL reduction. So very similar to what Evkeeza got in patients. So I think that's 40%-50% is what we'd be looking for, yeah. OK, and then the trial design here, bearing in mind you're also including two different populations? Right. So it's a single ascending dose design, very similar to the Heart-2 trial. This trial is called Pulse-1. It's testing the anti-ANGPTL3 editor, Verve-201. And basically, it's starting in this patient population called refractory hypercholesterolemia. So these are patients who have LDL that's too high on statin and potentially including a PCSK9 as well. And then in those patients, we'd be adding the anti-ANGPTL3 mechanism to try to get the LDL down. That's the group, refractory hypercholesterolemia. It's actually a reasonable fraction of patients with ASCVD. It's maybe anywhere from 10%-15% of patients with ASCVD on a statin plus a PCSK9 still have LDL that's too high. There's another group that's a rare orphan disease called homozygous familial hypercholesterolemia. It's about 3,000 patients in the U.S. and Europe. That's the other group we'll be approaching in this trial. Got it. So is it a staggered kind of a situation where you will try to nail down on the dose escalation and the dose selection part using purely refractory hypercholesterolemia and then move into HoFH? That's right. Because the HoFH patients are so few that you really like to get a handle on the dose, have at least a reasonable sense of the efficacious dose before you expose those rare homozygous FH patients. Then another checklist kind of a question. Would you have to go through the severe patients here, given that you're doing this for the first time using an anti-ANGPTL3 editor? No, we've made a lot of changes based on our experience to date, and so this is going to be the more moderate disease patients, yeah. OK, OK. So how should we think about the opportunity and pricing strategy, given originally my understanding was this is purely for HoFH? Now we add in refractory hypercholesterolemia, which probably expands that size a little bit. So it has implications on what the price point should be. I mean, is this something that you're still kind of catering towards a more rare disease type business model or something that's going to be a little bit more conducive to larger prevalent populations? I think it gets us to thinking about pricing and access for let's start with the PCSK9 program, because we get asked about that a lot. Now, most people think about in vivo gene editing as millions of dollars for the one-time treatment. That's certainly not going to be us for the PCSK9 program. Because number one, there are lots of patients. It's not a rare disease. And number two, the cost of goods. Our drug is mRNA packaged in lipid nanoparticle. This was our concept in 2018. Then COVID comes along in 2020. The COVID mRNA vaccines look like our drug. The COVID mRNA vaccines, mRNA packaged in lipid nanoparticle, cost 100 micrograms, cost about $5 to make. We're going to be giving like 50 milligrams for Verve-102. And that is low thousands cost of goods. So we're going to have a lot of flexibility based on the volume of patients and the cost of goods on how we price this thing. The way we've been talking about our medicine is less a drug and more like other one-time procedures in cardiovascular medicine that are permanent, intended for lifelong benefit, irreversible. And the best example of that is a coronary artery bypass surgery, open heart surgery. That's a one-time procedure, risk-benefit profile well understood, and lots of patients go through that procedure. For us, instead of actually having any surgery on the liver directly, you're actually having molecular surgery, essentially, with our procedure. A one-time infusion, you're changing a DNA letter in pretty much every liver cell. And so ultimately, we think our pricing might be more in line with those procedures. That's for 102. For 201, for ANGPTL3, we do have this rare orphan disease in addition to the more prevalent. And so I think we'll have maybe some different options depending on which indication kind of we choose to pursue first for registration. Okay. The thing about LDL is you want to keep it as low as possible for as long as possible, which I think I stole your line from our prior conversations. So when you think about sort of the complementary mechanisms of PCSK9 and ANGPTL3, I know the study populations are different now. But is there a convergence point where you're thinking about maybe having a single LNP that houses both the guide RNAs for ANGPTL3 and PCSK9, given the COGS implications aren't huge and they're both addressing larger populations? Is that something you're contemplating, or are you really splitting up 101/102 with 201? Yes. You are. Ok. Ok. Sounds good. So at this point, one thing that I also forgot to touch upon is the refractory hypercholesterolemia. How, from a biological and clinical standpoint, are they different in terms of efficacy that we can expect, right? Are they going to benefit more? Are they easier to treat in terms of bringing down the LDL versus a homozygous FH, or are they fairly comparable? I think I asked a similar question about the 102 program. I think that the best way to answer that is the degree of LDL reduction with Evkeeza in the two patient populations with the monoclonal antibody was identical. OK. Yeah. OK. So, their effect size, Regeneron did two trials, one for homozygous FH, one for refractory hypercholesterolemia. The LDL reduction with anti-ANGPTL3 monoclonal antibody was identical, like 49% in each group. Got it. So that's what we would expect as well. OK, OK. We're starting to run out of time. So maybe we'll touch on the cash part. But earlier, you talked about second half of next year is when the Lilly opt-in decision will happen. So remind us what needs to happen there, what kind of windfall you might get if they were to. Well, so remember, just to get people comfortable with the construct, so the PCSK9 program, at the end of phase I, Lilly has the ability to opt in. We give them a data package. They consider it. If they opt in, they'll be responsible for a third of worldwide development costs. In return, they get 50% of U.S. profits. The other 50% of U.S. is us, and then 100% ex-U.S. is us. So we retain majority economic rights. They have minority rights. Then we control development. We book revenues. And remember, these are rights that we had given to Beam, another party. And Lilly purchased those rights from Beam. And so that's the opt-in decision we think will be in the second half of next year and the economics as such, yeah. And in terms of our cash position, we ended last quarter with $540 million cash runway through 2026. So a strong balance sheet. And we'll get us through all of those events that I mentioned last year, initial data for 102 in the first half, the full dose escalation in the second half, the Lilly opt-in decision in the second half. We're continuing to enroll in the 201 program next year. And then we'll see where the data comes out for 201. By the way, what's the window that Lilly has to act on on the 101/102 after this event? Yeah. So after the last patient in phase I, we have some amount of time to put together a data package. They have some amount of time to decide. And we think all of that will end up happening in the second half of next year. Got it. OK. Well, thank you very much for your time. Thank you, Dae Gon Ha.