Verve Therapeutics, Inc. (VERV) Earnings Call Transcript & Summary

Senior biotech analyst with JPMorgan and our next presenting company is Verve Therapeutics. Presenting on behalf of the company is CEO, Sek Kathiresan. There's a Q&A after the presentation. Just raise your hand, we'll get a mic over to you. And then for folks joining on the webcast, feel free to submit questions there as well. Sek, over to you.

Thank you very much, Eric. Good afternoon. My name is Sek Kathiresan, I am Verve's CEO. In 2018, we started Verve Therapeutics with a concept for a new treatment modality in Vivo gene editing to treat cholesterol and heart attack and today I'm thrilled to tell you that it is working. 2023 was a momentous year for Verve, we established human proof-of-concept for In Vivo base editing and 2024 we expect to have 3 programs in the clinic. Over the next 20 minutes or so, I'm going to share with you the progress we've made to date and look forward to the year ahead. Some forward-looking statements and disclaimers related to that, and I'll be making a few forward-looking statements. Overall, we're on a mission to protect the world from cardiovascular disease and we're working with a treatment concept of onetime intravenous infusion procedure leading to lifelong cholesterol lowering. That's what we're trying to accomplish with single-course gene editing medicines. Let's start by looking first at the problem. What causes atherosclerotic cardiovascular disease and what might be a solution? The causes are shown on the left. High cumulative lifelong exposure to blood cholesterol clogs the heart arteries and leads to heart attack. The cholesterol is carried in any of 3 lipoproteins shown on the bottom left, LDL, triglyceride-rich lipoproteins or TRL or lipoprotein (a), what might be a solution to atherosclerotic cardiovascular disease? That's shown on the right. The solution is to keep blood cholesterol as low as possible for as long as possible. It's not only how low you lower the cholesterol but also how long. How is ASCVD treated today? And is there still an unmet need? The current treatment options to lower LDL cholesterol, all lower LDL by about 40% to 60%. Shown in the graph on the x-axis is time on cholesterol lowering treatment, on the Y-axis is the LDL cholesterol for a hypothetical patient with a genetic condition called familial hypercholesterolemia. This is a condition where the cholesterol is sky high from birth. What you can see is statins or PCSK9 siRNA or PCSK9 monoclonal antibodies, each lower LDL by about 40% to 60%. These medications are intended to be taken lifelong. However, up to 50% of patients discontinue CVD medications within 12 months of initiation. This means for many, the real-world LDL cholesterol lowering is not 40% or 50% or 60%, but closer to 0. This is the unmet need that we're trying to solve. Shown on the right are some of the key facts around this unmet need. About 50% of atherosclerotic cardiovascular disease patients are not on a statin. Only about 2% of eligible patients are currently on a PCSK9 agent and only about 3% of patients with heterozygous familial hypercholesterolemia, that genetic disease I mentioned earlier, are at LDL goal. So how might we address this unmet need? What we're trying to develop is a new treatment option, a onetime intravenous procedure that leads to lifelong cholesterol lowering. And what might the differentiation be for this kind of treatment compared to what's already available for cholesterol lowering? The differentiation features are listed on the right. First is single treatment versus chronic dosing versus chronic care. The second, our goal is broad access for this highly prevalent disease, remind you that heart attack is the leading cause of death in the entire world. Lastly, this kind of product, which is an RNA packaged in the lipid nanoparticle is now precedented for mass use. Now will patients be open to a onetime gene editing procedure as a solution to heart attack and high cholesterol? Here's an example of a patient preference survey that actually shows a remarkable openness to this kind of approach. This is a survey taken of about 500 individuals with atherosclerotic cardiovascular disease, and there's an assumption here that they all require lifelong therapy for the treatment of their high cholesterol and/or cardiovascular disease. The patients were asked to list their preference among 4 choices: a once-daily pill, a onetime gene edit, twice annual injections performed at the doctor's office or twice a month injection self-administered. And 35% of patients preferred a onetime therapy for their cholesterol lowering. Based on this kind of openness, Verve is developing a pipeline of In Vivo gene editing programs designed to lower cholesterol lifelong after a single treatment. Several features of our pipeline; first, are the targets. Each of the 3 targets PCSK9, ANGPTL3 and LPA have compelling human genetics validation. Humans who completely are deficient in each of these proteins have been identified. They have lifelong low cholesterol levels, they're protected from heart attack and are healthy. In terms of the indications, you can see a general pattern where we start with a genetic form of the disease, followed by expansion to larger populations for each of the first couple of targets. And on the third column you see the technology that we're using. And the main point I want to make here is that we're flexible as to the gene editing technology that we're going to be using for each of these targets. For the first couple, we're using base editing but for the remainder, we're actually developing custom, bespoke editing approaches customized for that target. In addition, our pipeline involves distinct -- sorry, our programs are designed to address distinct groups of patients with ASCVD, and that's listed here. There are largely nonoverlapping sets of individuals. And again, this theme of starting with a genetic form of the disease, HeFH or HoFH, followed by expansion to larger patient populations. And overall, it's a very large addressable market, over 50 million people in U.S. and Europe with ASCVD who require lifelong cholesterol lowering. As I said earlier, 2023 was a momentous year for Verve and the key accomplishments are highlighted here. We developed human proof-of-concept for In Vivo base setting technology. We developed 3 product candidates against highly validated targets, ASCVD targets that I'll talk about. We also developed novel GalNAc lipid nanoparticle delivery technology with a potential for improved potency. We established a regulatory path in the United States with FDA/IND clearance for VERVE-101, our lead product. Finally, we -- through business development as well as a secondary offering, we added to the balance sheet and now have over $600 million in cash and our runway into late '26 to be able to advance our pipeline. In '23, we also established a relationship with Eli Lilly across multiple programs. Some of the details of those economic arrangements for the programs are shown her, but what I want to emphasize is Lilly is an ideal partner for us as we think through late-stage development and commercialization of our cardiovascular medicines. Let me now turn to each of the targets in turn, PCSK9, ANGPTL3 and LPA. First, PCSK9. VERVE-101 is a novel base editing medicine designed to inactivate hepatic PCSK9 and lower LDL cholesterol with a single DNA base pair change. The product consists of an mRNA for the base editor and a guide RNA that localizes the PCSK9 gene and both of these RNA molecules are packaged in a lipid nanoparticle that is shown in the middle. This product is delivered as a onetime intravenous infusion taken up by hepatocytes. Ultimately, the editor makes a single A to G spelling change in the DNA of the PCSK9 gene sequence to turn off the gene. Turning off the gene lowers blood PCSK9 protein level and consequently lowers blood LDL-cholesterol level. VERVE-101 has been tested in a Phase Ib study called Heart-1. This trial is designed to evaluate the safety and tolerability of VERVE-101. It's an open-label trial, a single ascending dose design with endpoints of safety and tolerability as well as PK and blood PCSK9 and LDL measurements. As of the interim data cutoff date of October 16, 2023, 10 participants have been dosed across 4 dose levels shown on the bottom right. The participants enrolled to date have had severe advanced atherosclerotic cardiovascular disease and high risk for cardiovascular events in the near term and over a lifetime. Here are the interim data for efficacy. On the left is PCSK9 levels, on the right is LDL reduction. Overall, the main message is it worked, VERVE-101 led to dose-dependent reductions in blood PCSK9 and blood LDL with clinically relevant LDL reductions achieved at the higher doses. First, focus on the left on the PCSK9, shown on the Y axis is the degree of reduction in PCSK9. Each bar represents a different dose level and the bars represent cohort averages, each individual dot is a participant. In the first 2 dose levels, very minimal reduction in blood PCSK9. But at the 0.45 and 0.6 mg per kg doses, that's the purple and the blue bars, you see PCSK9 reductions ranging from 47% to 84%, really considerable reduction in blood PCSK9. On the right is the blood LDL level. You can see at the 2 potentially therapeutic doses in blue and purple, you're seeing blood LDL reductions of 39%, 48% and 55%. Now what about durability? Remember, I mentioned earlier the key differentiating feature of our medicines are the prospect of onetime treatment lifelong LDL lowering. Where are we with that? Shown here is the durability. On the X axis is time after treatment on the Y axis is the degree of LDL reduction. In the single participant at the 0.6 mg per kg cohort who's been followed the longest, the 55% reduction in LDL seen in the first few days, that's the purple line, now extends to 180 days after treatment. So a onetime treatment, 6 months later, the LDL is still down 55%. These data are reminiscent of our data in nonhuman primates, where after a single treatment, we were seeing durability out to 2.5 years in monkeys. Here are the interim safety summary. The observed adverse events are consistent with severe advanced ASCVD patient population. We saw infusion-related reactions at doses greater than 0.45 mg per kg. We saw transient reversible increases in liver function tests and cardiovascular SAEs in 2 participants. All safety events were reviewed with an independent data safety and monitoring board who recommended we continue the trial enrollment with no protocol changes required. Of note, these clinical data were also reviewed by the FDA prior to giving us clearance to start the trial in the United States. So overall, Heart-1 trial demonstrated the first proof-of-concept for In Vivo DNA base editing in humans. So it really is now possible to make a spelling change in nearly every liver cell in a living human being for clinical effect. What are the next steps in the Heart-1 trial? We're continuing to enroll in 0.45 and 0.6 mg per kg cohorts to complete the dose escalation phase. We are transitioning to patients with less advanced, more moderate disease. In addition, we are looking to open U.S. trial sites for additional patient enrollment now that we have an IND clearance. We expect to complete enrollment for the Heart-1 in 2024 with an additional data release planned in the second half of 2024. Let me now move to a second product concept for targeting PCSK9. This is called VERVE-102. VERVE-102 contains the same active ingredients as VERVE-101 in terms of the mRNA and the guide RNA. But the 2 RNA components are packaged in a different delivery system, one that contains a targeting ligand called GalNAc. So the main difference is a delivery vehicle. 101 and 102 differ in 2 ways in terms of the delivery vehicle. First is the LNP contains a different ionizable lipid. Second, the LNP contains a GalNAc targeting ligand that allows the LNP to enter into hepatocytes by any of 2 receptors, LDL receptor or ASGPR. By virtue of this, we might expect VERVE-102 to be potentially even more potent than VERVE-101 when given to patients. Now VERVE-102 has demonstrated really nice durable LDL reduction in nonhuman primates. The data looked quite good and comparable to VERVE-101. So we have 2 products that have excellent efficacy and safety in nonhuman primates. So the question was how to pick between the 2 for development. And our strategy over the last couple of years has been to test both in patients prior to selecting one to take forward to later stages of development. Based on that strategy, we are in the process of initiating a Phase Ib study for VERVE-102 in the first half of this year. The patient population and the study design are largely similar to the VERVE-101 trial. Here is a time line of the simultaneous development of VERVE-101 and 102, followed by selection of 1 of the 2 products to take forward into Phase II. After data for 101 this year and 102 next year, we expect to take 1 of the 2 forward into a Phase II in 2025. This Phase II should be a randomized controlled study with a placebo component as well. Let me now move to the ANGPTL3 program. VERVE-201 targets ANGPTL3, a compelling target with human genetics and human pharmacology validation to lower LDL cholesterol by a mechanism that's additive to PCSK9 inhibition. Shown on the left is the human genetic data. Humans with ANGPTL3 deficiency have very low levels of LDL, very low triglycerides and are healthy. So this makes it a very compelling target. On the right are the human pharmacology. A monoclonal antibody targeting ANGPTL3 has been shown to lower LDL in 2 patient populations, a rare orphan disease called homozygous FH, where the drug is actually FDA approved and another population called refractory hypercholesterolemia. These are patients who have high LDL despite taking a statin and a PCSK9 inhibitor. In both these patient populations, treatment with a monoclonal antibody targeting ANGPTL3 lowers LDL by about 50%. We've generated preclinical data in nonhuman primates to model that genetic disease of homozygous FH. This is data on the left showing nonhuman primates where the LDL receptor has been knocked out in the liver to dramatically increase the LDL in these animals to mimic homozygous FH physiology. And then we came in with the ANGPTL3 product, VERVE-201 and we were able to show is we could edit the liver, lower the blood ANGPTL3 level and subsequently lower LDL by about 46% in this monkey model of homozygous FH. These preclinical data and others like it have us poised to start a Phase I for VERVE-201 in the second half of this year. The LPA program is what I'll describe next. This is a research stage in collaboration with Eli Lilly, we're advancing a potential genetic treatment for elevated LPA. Elevated LPA is a large addressable market, about 11 million patients in the U.S. and EU with high levels of LPA. On the right, highlight some of the reasons why there's significant potential for a once and done gene editing medicine for this marker. Humans with genetic LPA deficiency are resistant to heart attack and stroke, and there's no signal for adverse events. Now the blood level of LPA is almost entirely determined by inheritance by genetics. So it's really a genetic disease. Lifestyle factors and other medicines like statins had minimal impact on LPA and therefore, the idea of a onetime therapy to permanently turn off the LPA gene and lower blood LPA is very attractive. As I said, research efforts are ongoing to develop a bespoke gene editor tailored to target LPA. In 2024, we'll have 3 In Vivo gene editing programs in the clinic, VERVE-101, VERVE-102 and VERVE-201. And these clinical stage programs are the focus for Verve in 2024. Now what can you expect from the company for 2024 and 2025? Here are the milestones we're guiding to. On the left is 2024, and let me start with the PCSK9 program. We expect to initiate a Phase I for VERVE-102. And for VERVE-101, there are 3 items. One is dose the first U.S. patient, complete enrollment in Heart-1 and the data update for Heart-1. For the ANGPTL3 program, we'll be initiating, as I said earlier, Phase I for VERVE-201 in the second half of this year. For 2025, the key goals are really to select either VERVE-101 or 102 to take forward to a randomized controlled Phase II and then for the PCSK9 program, a data update for VERVE-201. Overall, we're well capitalized with over $600 million in cash and runway to -- and a runway into late '26 to achieve all these milestones. So we started the company in 2018. We've gone from concept to proof of concept in humans in just 5 years for a brand-new treatment modality and really can't wait to see what the next few years will bring for Verve as we work on our mission to protect the world from cardiovascular disease. Thank you.

We are starting the Q&A session and as a reminder, we'll bring a mic around for folks in the room that have questions. Sek, I guess following the AHA presentation of Heart-1, I'm just curious to get a sense of what the physician feedback has been like so far, particularly around the -- really in the -- around the clinical profile that you're presenting so far, not only on PCSK9 and LDL lowering, but also around just the safety profile given some of the ALT signals that -- and also some of the other -- what are patients also experiencing a potentially treatment-related cardiac event?

Yes. I think the physician response actually has been very enthusiastic in terms of the clinical -- potential clinical impact here, essentially opening the door for an entire new way to treat heart disease rather than daily pills, intermittent injections, a onetime therapy, lifelong cholesterol lowering. In terms of the specific adverse events, in terms of LFT elevation, there's -- as I mentioned, there's a transient rise in ALT that comes back down to normal over a couple -- few days without evidence of injury and reversible, monitorable. So quite manageable for a onetime therapy and so this didn't bother us and it hasn't bothered most clinicians who have looked at this. In terms of the cardiovascular events, again, this is an open-label trial in patients with severe advanced disease, so really the sickest of the sick. And that's what we were guided to in terms of an initial patient population for a brand-new treatment modality, human genome editing. But the FDA also recognized with that guidance, that treating such advanced patients, these patients might have -- might be more likely to develop AEs, making safety more difficult to interpret. And they noted that therefore, it might be appropriate to move to less advanced, more moderate disease patients as you get experience and that's exactly what we're doing in this study and going forward. So I think the response overall from physicians has been quite positive, actually.

So as you look to sort of expand the study enrolling sort of less severe, less high-risk patients going forward, I guess what -- how you're adjusting sort of the screening or eligibility criteria to some -- is just one facet of the question. And I mean, I presume commercially speaking, I mean a good set of the population that you want to pursue are actually patients that are in need of a therapy like this because they've had a prior MI perhaps. So I guess, how do you make sure you're kind of getting -- you're studying 101 or 102 in the population that sort of represents the real -- the population that you probably want to target here in the commercial setting?

Yes. I think that in terms of how we're moving to less advanced patients, and this is really for the Phase I, where it's an open-label study, right, Phase I. So that's where without a control group it gets more challenging to kind of think about safety. So for the Phase I, we are making 2 changes to get to less advanced patients. One, is that we have included a screening coronary CT angiogram. So this is a noninvasive test, a die test that looks at the heart arteries for blockages, and we're using that to exclude patients who have critical severe blockages. So that's one. And so overall, the other is that right now, patients have heterozygous FH and evidence of atherosclerosis, and that evidence requirement has been clinical events, either a prior heart attack or bypass surgery or stent. And you can see from the patients we've enrolled to date, many of them have had multiple heart attacks prior to coming into the study or multiple procedures. And going forward, patients can come in with evidence of atherosclerosis just on imaging. So plaque on imaging plus heterozygous FH can now -- those patients can now be included. So these 2 changes, I think, will allow us to transition to less advanced, more moderate disease patients in the Phase I where there isn't a control group. As we move forward, Eric, into Phase II and Phase III, where we expect to have a control group that receives placebo where we can actually monitor the event rate in both groups to look at a treatment effect impact on CV events, we will be broadening and removing these restrictions to get to patients who have already had an MI and so forth.

Can you talk a little bit about further dose optimization with VERVE-101 going forward? I guess a couple of things. One is that there perhaps seems to be a bit of a disconnect between LDL lowering and PCSK9 -- lowering, I guess, with the caveat of yes, a low end. And then also just kind of having to navigate perhaps some of the tolerability or risk of AEs perhaps as you dose [indiscernible], I guess -- I guess, do you expect to kind of continue dosing [indiscernible] with 101 at the same time also evaluating 102?

For 101, the 2 potential therapeutic doses, 0.45 and 0.6, we only dosed 3 patients across those 2 doses. So it's a very small end right now. So the main goal is basically to flush out those 2 doses and just enroll more patients at 0.45 and 0.6. So that will give us a sense of where we are in terms of PD and editing an LDL reduction. In terms of your question about the relationship doing the degree of PCSK9 reduction and the degree of LDL reduction, there is a linear relationship at the population level. So when you look at hundreds of patients or even thousands of patients. And any given individual actually, there can be variability on what degree of PCSK9 reduction leads to what degree of -- some degree of LDL reduction. So that's, I think, what we're saying and what we're seeing here. So I think a lot of this will just be sorted out by dosing additional patients. The main goal of this Phase I is to select a single dose to take to dose expansion. And so by completing the dose escalation this year, we'll be able to pick 1 of the 4 doses likely to take to dose expansion in '24.

And you -- regarding VERVE-102 in that Phase Ib trial, you kind of noted being operationally and similar to that of the Heart-1 study, at least in design. So I guess one thing to think about it from the operation of that study, I guess should we -- I guess, where do you anticipate U.S. site participation in that study from launch? Or would it kind of follow a similar sort of... Exactly, enrollment pattern beginning in ex U.S.

Yes. No, I think we expect to start 2 ex U.S. as well and then move to U.S. And -- but for 102, we are -- we do have a broader geographic footprint both site-wise and country-wise for 102 compared to 101. So that's one of the key differences. The study design is quite similar, and this patient population is quite similar but the geographic footprint is going to be larger and I think that will allow us to kind of meet some of these time lines.

I guess looking further out and just thinking about sort of where 101, 102 will ultimately be positioned within the -- be positioned commercially among a number of PCSK9 lowering agents. I mean, certainly, the onetime optionality of your approach has a lot of -- it was desirable. I think that's clearly apparent. Nevertheless, for perhaps payer considerations there may be a little bit of a pushback or maybe some hurdles perhaps that patients may need to step through in order to have access. Is there perhaps a distinct patient population that -- where your approach might be sort of more readily reached for compared with the chronic PCSK9 lowering agents?

I think the development plan that we've shown, which is starting with heterozygous FH, that patient population is very high risk. They have very high LDL from birth, often have heart attack 30s, 40s, so very young, it's a severe disease. And often, the first heart attack is fatal and those patients are not being well served right now. The current agents, yes, they theoretically lower LDL, but nobody is on them. So the LDL lowering is 0. Only about 2% of patients actually are a goal, 3% actually FH patients worldwide. So I think a lot of those patients might be very well served by a onetime therapy that dramatically and durably lowers their LDL. And that's about 3 million patients in U.S. and Europe alone. So that's a very large genetic disease. And to be honest, if that's the only problem we ever solved in the -- with our medicine, it would be pretty impactful. Now we have broader ambitions to go even broader to ASCVD. But FH is a great starting point. And I think the one point that it's kind of underappreciated of the product profile that we're trying to get to is not just about convenience, about you're only administering at once versus having to do it multiple times every year or hundreds of times over your lifetime. It's actually about clinical benefit because this disease is about cumulative exposure to LDL, how much LDL are you exposed to over your lifetime. And that's a function of the LDL and time. So it's really area under the curve. And right now, patients are not being well served in terms of that reduction in that cumulative exposure of kind of cholesterol years. They might get reduction for 6 months, 12 months, maybe even 2 years, but they're not going to get it for 30 years consistently, and that's the challenge right now. That's the unmet need that we're trying to solve.

I remember following your Twitter before you joined Verve and I really enjoyed it. So I remember that. But I have a few questions. What percent of the targeted sales did need to be edited in order to achieve your clinical effect? And I know you're targeting one-time therapy, but is it possible to dose again in the future, perhaps for maintenance? And third -- last question is, like for gene therapy, we have vector genomes per kilogram. So it's very easy to see -- very easily describes quantity, particularly when I'm comparing head to head and just for titers, -- how should we consider or how should we think of your delivery packaging construct and the milligram/kilogram dose to conceptualize how much -- how many you're actually delivering?

Yes, that's a great question. Great set of questions. On the target cell, what we're actually achieving right now is we're editing at least nonhuman primates at the relevant doses nearly every hepatocyte because we're essentially bringing down in nonhuman primates, blood PCSK9 by anywhere from 80% to 90%. And overall, in the blood, about 80%, 90% of the blood level, I should say, comes from the liver. So we're basically getting rid of all the stuff that's coming from the liver and nonhuman primates. And at least in that one participant, we got it down to 84%. That suggests that we're editing nearly every hepatocyte -- both alleles to turn the gene off completely in the liver. So that's the degree of editing we're getting. And in the case of PCSK9, you really want to get it as low as possible. So we are trying to get to kind of saturation editing. In terms of redose, yes, it's possible with liponanoparticles. We've shown that in nonhuman primates, and others are now starting to show that in humans as well, particularly in [indiscernible]. And then in terms of the measurement of the editing, you can measure the RNA component of the drug to give you a sense of what you're delivering in terms of the editor.

Okay. I think we'll have to leave it there for time. So thanks very much Sek for your presentation and the Q&A session. Everybody have a great afternoon.