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

Welcome, everyone, to 2025 Jefferies Global Healthcare Conference. My name is Roger Song, one of the senior analysts cover SMid-cap biotech in the U.S. And then it's my pleasure to have the next fireside chat with our company, Sek from -- excuse me, from the Verve Therapeutics. So it is a very exciting timing for Verve because they just reported a very exciting data from the VERVE-102 for ASCVD to lower PCSK9 to lower PCSK9 to lower the LDL-C. Maybe we can start from there. But before that, Sek, can you give us some elevator pitch for Verve in the high level with the recent updates?

Yes. Thank you so much, Roger. Thanks for the invitation. Pleasure to be here. So Verve Therapeutics is focused on atherosclerotic cardiovascular disease. ASCVD or heart attack, maybe many of you know, is a leading cause of death in the world. A key driver of that problem is LDL cholesterol. And a key potential solution to heart attack is to get the LDL as low as possible for as long as possible. And that really looks like it's a really important answer to the problem. We have a lot of treatment options right now to lower cholesterol, but there's still a huge unmet need because the majority of individuals who get started on a cholesterol-lowering medication at 1 year time point after initiation, about 50% of patients are no longer on any LDL-lowering medication. So that's a huge issue if you're really thinking about having to have this LDL lowered for a long time, for a lifetime. So that's the unmet need that we're trying to address at Verve with a onetime therapy that would actually lower LDL lifelong after that single treatment. We started with that vision in 2018. And then this year, a couple of months ago, we showed Phase I data for VERVE-102, our molecule basically that delivers a gene editor, base editor to the liver to make a single spelling change in the DNA sequence of the liver in the PCSK9 gene to turn it off. Turning off the PCSK9 gene lowers blood PCSK9 protein and thereby lowers blood LDL. What we were able to show in this Phase I data set about 14 patients across 3 dose levels is that a single intravenous infusion of our drug product, VERVE-102, delivered with a peripheral IV over 2 to 4 hours, basically led to dramatic and durable reduction in both PCSK9 level and blood LDL level. The magnitude of the LDL reductions at the highest dose level, the mean was about 59% LDL reduction and the max of 69% and every participant in that high-dose group had over 50% reduction. And then in terms of durability, we showed data in April for an earlier version of the product called VERVE-101, where had the same editor. And with the editor, the base editing mechanism with the onetime infusion, we were able to get the LDL down about 60%. And then 2 years later in that individual, the LDL was still down 60%. So really suggesting that this mechanism that we probably can get to this vision of a onetime treatment lifelong cholesterol lowering. So that's the Phase I data. And importantly, I mentioned the efficacy, but maybe even more important is safety. The safety profile after the infusion was excellent, clinically well tolerated, no clinically significant laboratory changes in either liver or other blood parameters. And so it really gives us a very encouraging profile to continue to develop. We are continuing in the dose escalation in the Phase I right now. and with the goal in the second half of the year, Roger, to deliver the full dose escalation results as well as we have an exciting partnership with Eli Lilly, which we can talk more about where we expect them to opt into the program in the second half of the year. So those are really the key milestones for this program, the lead asset in the second half of the year.

Excellent. Okay. I think that's a good overview for the recent updates. Maybe we can drill down a little bit for the Phase I data. It seems you are -- I think you publicly said that well, you are starting to design the Phase II, so which means this Phase I absolutely supporting the next step. And then one of the key aspects is the dosing, right? It seems in the Phase I, you have something like the total RNA dose versus weight-based dose. So tell us a little bit more about that. What's the thinking to design the Phase II dose?

Yes. So I think one of the observations coming out of the dose escalation is how should you deliver this drug. And so there are 2 ways to think about it. One is weight-based, so milligram per kilogram. That milligram -- in the milligram per kilogram refers to the total weight of the RNA, the cargo that's carried by the lipid nanoparticle. And so if you have, for example, a 0.6 mg per kg dose, a 60-kilogram person would receive 36 milligrams of RNA, 100-kilogram person would receive 60 milligrams of RNA. What we found in the dose escalation so far is that the milligrams of RNA received by that individual seems to be the key driver of pharmacodynamics. And if you now think about it holistically, it kind of makes sense because this drug when delivered into the body through the blood system -- bloodstream, almost all of it goes to the liver right away. So you're really just treating the liver. And so the milligram dose of RNA is really probably the best way to capture how much you need and what drives pharmacodynamics. So as we move to Phase II, we likely will transition to fixed RNA doses. And this is what's happening for most of the in vivo gene editing field. There's a transition from mg per kg dosing to fixed dosing.

Yes, that makes sense because you also see the dose dependence very clear. So with a higher total RNA dosing and your efficacy is...

Yes, we saw a near linear relationship so far between the milligrams of RNA delivered on the X-axis and the degree of LDL reduction on the Y-axis.

Excellent. And then as you mentioned, this is a onetime gene editing therapy. Efficacy is on the one side, but safety also pretty paramount there. You are very confident about the safety profile you see so far. We got news from the Intellia a couple of days ago, understanding they're using the similar RNA LNP delivery license from Novartis. And then just tell us a little bit about the history of the LNP delivery from your first gen to second gen. What's the modification you have done for that delivery? And then why you are confident your LNP delivery will be safe tolerated?

Yes. So for VERVE-101, which is our first-gen product, we had a certain ionizable lipid that we used. Ionizable lipid is 1 of the 4 chemical components that go into a lipid nanoparticle. Remember, lipid nanoparticle are these little fat bubbles that basically carry cargo in the middle. In our case, it's RNA cargo, and that's how the drug is ultimately delivered to the liver. We use a certain ionizable lipid. In VERVE-102, one of that chemical component has been switched out to a different sources from Novartis. In addition, for 102, the next-gen molecule, we've added a liver targeting ligand called GalNAc. And then we have a proprietary process as how do we put all those components together. And so that's 102. What gives us confidence on the safety, of course, is our preclinical data, but also the clinical profile that we're seeing where within the first 14 patients dose, as we escalated, we didn't -- we have not even seen any dose-dependent increases in liver function tests, for example which sometimes you see with lipid nanoparticles. So we feel very good about it. In terms of the relationship to the Intellia product and the safety observation they had, one thing to note is that there are really 2 patterns of liver function test elevation that Intellia has noticed with their product, which is a lipid nanoparticle delivering a Cas9 nuclease for TTR, a rise in the first week or so, so-called early in ALT and then what they reported last week, which was late. So the onset was late and the peak was at day 28. Now -- and they commented last week that, that pattern, the late rise is unlikely to be due to lipid nanoparticle because the lipid nanoparticle related infusion -- problems or challenges happen typically, as I said, in the first week and are -- because the lipid is there only for about a week. So the question is, what is this late due to? It's unlikely in our view to be LNP related in Intellia's view as well. So we believe there's probably limited, if any, read-through to us. And so I think we'll have to see what hypotheses Intellia puts out regarding why they are seeing this late rise.

Yes. It's a different cargo and a different indication. Probably that's related to -- unlikely related to the [ LNP ]. Yes. Got it. Okay. This program is -- moving forward, you have a couple of things upcoming, right? So one is you will give us the full data later this year, and they will start the Phase II. And then you will -- your partner, the Lilly will make the opt-in decision with the Phase I package. Just tell us about the sequence of those events and then what have been happening along the way? What's the key consideration for Lilly to make the opt-in [indiscernible] decision?

Yes. So I think the sequence will really be -- we put out data for the first 14 patients across 3 dose levels. We're continuing to escalate to the next dose level. The full dose escalation data in terms of safety, LDL, PCSK9 reduction and durability, we expect to deliver in the second half of the year. That's probably the first event, a data disclosure, full dose escalation. The second after that will likely be hopefully an opt-in decision from Lilly. We expect them to opt-in and that disclosure. And then third is dosing of the first patient in the Phase II. So we're guiding to that happening this year as well. So those are the 3 main milestones for the VERVE-102 program and the [ HER2 ] trial. In terms of Lilly opt-in, the mechanics there, the contractual mechanics are we have -- with the last patient dosed in the Phase I that starts a clock. We put together all of the clinical data, the preclinical data, a budget for development as well as the clinical development plan and present that to them. They have some time to review that and then make a decision. As I said, there -- we've been talking to them all along. We have quarterly JSE meetings. We have a good understanding of expectations in terms of the data from their end. And so -- and they've invested a bit already, as you know, in terms of purchasing these rights from Beam Therapeutics a couple of years ago. And we believe they'll opt-in, in the second half of the year based on the data we've generated.

Okay. Good. And then just zooming for those 3 events seems to be pretty meaningful for you for the second half. And then for the full dose, understanding you are dosing the potentially last cohort, 0.7 dose cohort, what do you hope to see? Because right now, so far, data profile is already supporting the next step. So what do you want to see safety-wise and LDL reduction-wise?

Yes. So you're exactly right. I think the profile that we showed for the 50 to 60-milligram group was a mean reduction of 59%, a max of 69% LDL reduction. And then every individual in that group, all 3 individuals had over 50% reduction. So that's a great profile. I think -- but we're -- as you said, we're escalating to the next dose. The main reason is, right now, if you look at the milligram RNA on the X-axis and the degree of LDL reduction on the Y-axis, it's a straight line down right now. It's a linear relationship. And so the question is, where will it transition from a linear relationship to a plateau? And since we still have headroom, it seems like on the safety side, could it be that at this next dose level, we get even more consistent reduction at a higher average than what we had. If so, that would be really important to know. So that's the reason to really to kind of continue the dose escalation. And remember, this is our one chance to really understand the full dose response. And because once you select a dose or 2 to take forward to Phase II and then maybe -- and then one to Phase III, you're kind of like limiting yourself. And this is a very large indication. We really do want to understand the full dose response at this stage.

Absolutely. And then based on your preclinical or some PK/PD modeling, you think the next dose cohort will likely be the highest dose cohort you want to test?

We have to see how it translates. We do have the flexibility in the protocol to even add an additional dose level if should we want that. But right now, we're focused on the current dose level.

Yes. Makes sense. Okay. And then moving on to the Lilly decision. It seems Lilly already start to have -- they always have a conversation with you, but also they are starting to give some inputs around the Phase II design. So just tell us a little bit about the interaction with Lilly. And then you mentioned they have a pretty good idea of what profile they want to look at it, how much you can tell us?

Yes. No, I think we have a very good relationship with them. I think it started a couple of years ago during the process where they acquired the rights from Beam. And I think there's good alignment on the cardiovascular space, what are the important targets in the cardiovascular space. They share our enthusiasm for PCSK9, ANGPTL3 and LPA. There's also alignment on this idea that cardiovascular care down the road will end up being essentially a multimodality pipeline for each of the major important targets. And so you can kind of see that playing out in the way Lilly is approaching LPA. It's an important target. They have an oral molecule, a small molecule in Phase II, finished Phase II. They have an siRNA that's right now in Phase III. And then they're working with us for a gene editing option, a one-and-done option for LPA. And so this is emblematic of, I think, where the field is headed. These are very large indications. You can have in the market at the same time, multimodality pipeline and there will be different choices made by different patients, providers and payers. And there's room for all because the indications are so large. And you're seeing that in GLP-1, for example, for them. They have a pill, they'll have different injections of different frequencies, combinations with incretins. So there's very good alignment with Lilly on all of this. In terms of the specifics of the 102 program, I think our TPP, which is really LDL reduction greater than 50% and do it safely and have it durable for a long time, that is a compelling TPP that they've bought into, and that's what we're looking to deliver with the data package.

Awesome. Great. And then in terms of the Phase II, given all the changes happening on the FDA CBER side, so what's your current thinking around the next step into the Phase II and even forward in terms of the registrational path? How much you have discussed with the new FDA?

Yes. So we've had very good interactions with the FDA, even with the new group, new leadership. We had an IND cleared for 102 just very recently. We received a Fast Track designation. And as you know, Fast Track is given when the FDA sees a high unmet need for a serious disease. And so certainly, given that atherosclerotic cardiovascular disease is a leading cause of death, it's a serious disease. And there's still, as I mentioned earlier, still a huge unmet need despite all the cholesterol lowering therapies available right now. So they see that. So we -- and so I've characterized our interactions really as kind of business as usual. And then in terms of going forward, with the open IND, we're able to kind of move forward into the Phase II by just notifying the FDA of kind of what our intentions are. We also have a global footprint for Phase I, and we continue that for Phase II. So we're in multiple geographies, U.S. included. And then in terms of registration path, our base case is LDL as the registration endpoint. It's an incredibly well-accepted endpoint, very close tracking with clinical outcomes, probably the best validated biomarker in all of medicine. And there's been a very recent precedent for a new technology inclisiran, siRNA for cholesterol, LDL cholesterol, that the registration path included a Phase III study in about 500 people for HeFH, heterozygous FH, our lead indication, and then 2 additional studies, LDL-based studies for atherosclerotic cardiovascular disease. So that's really our base case. LDL-based studies, approval based on that, on the market based on that. And just to note, inclisiran, also called Leqvio is on the market right now based on that registration from those studies and this year is expected to have revenues greater than $1 billion. So that's really our base case.

Makes sense. Okay. You mentioned Lilly is using -- trying to do multiple different modalities for the same target, maybe similar population. And then given this is a potential new modality. So how do you think about the real addressable market for the future 102, particularly what will be the initial adopter -- early adopters and then versus later, people can expand to the broader population, given HeFH still pretty big and let alone the ASCVD.

Yes. So we've -- just to give you a sense of the market opportunity, HeFH is about 3 million people in U.S. and Europe. It's the genetic disease, sky high LDL from birth inherited from parents. Second is ASCVD. That's about 25 million people in U.S. and Europe. So these are very large indications. Early adopters, I think, are going to be in this group that we're focused on for our Phase I actually, which is HeFH patients. And then the patients with ASCVD who happen to have had an event at a young age. So men less than 55, women less than 65 who've had a heart attack. And about 20% of all heart attacks happen in that age group. And so the reason these are -- we think are going to be the early adopters is that these are patients who require 30, 40 years of LDL care. So daily pills for 40 years or twice a month injections for 40 years. That kind of -- that's very burdensome and that's the unmet need. It's basically not happening right now. About 50% of people no longer on any of these medications at 1 year for a medicine that's supposed to be taken for decades. So we're -- these are the -- and then we've done market -- we've done patient preference surveys as well as physician preference surveys. And the results of those align with what I just said, younger patients, patients who are facing decades of care, patients with genetic disease are the ones that I think will be early adopters.

Excellent. And then so this population, when we think about they will be the early adopter, and then what -- do you think those are potentially can have any other competitor modality? Can I also address that in terms of maybe a little bit more frequent, but also they have some good efficacy and safety...

Yes. I mean just to give you -- we do think there will be a marketplace full of options, right? But -- so we've surveyed patients in terms of a future treatment landscape that includes a daily pill, twice a month injection, twice a year injection, a onetime therapy, all for LDL lowering and all potentially targeting PCSK9. And about 1/3 of patients surveyed preferred the onetime therapy. And if you ask physicians, cardiologists, for about 40% of their HeFH patients, they would prefer a onetime therapy. And for about 20% of their ASCVD patients, they prefer a onetime therapy. So there's, I think, a lot of openness to this kind of approach. And I think one other idea on the market opportunity in commercial that we get asked about quite a bit is pricing. And I think that's actually another area where we're going to be quite different in terms of gene editing gene therapy compared to other targets or other companies. And this has to do with the fact that most people think this kind of approach is going to automatically be hundreds of thousands of dollars for a single dose or millions of dollars for a single dose. That's unlikely to be us because we're not rare disease. We're actually very common -- as I mentioned, very common disease, lots of patients. Second, so we don't have to resort to rare disease pricing. Second, the cost of manufacturing here can be quite manageable at scale. This kind of product, RNA package and lipid nanoparticle, 100 micrograms, we now know because of the COVID experience, this kind of product can be made for about $3 for 100 micrograms. Now we're going to be giving more like 50 milligrams. But if you just multiply up, it's like $1,500 cost of manufacturing for a single dose. So that's going to give us a lot of flexibility on pricing. And I think the way to think about pricing for this kind of product is going to be like other onetime procedures in cardiovascular medicine. So think bypass surgery, for example, another onetime procedure, permanent, irreversible, intended for lifelong benefit. Lots of these are done every day, and they have price points way different from what people think about in terms of gene therapy.

Yes. Given the scale and also the potential market opportunity, you are priced not as real rare disease gene therapy type of pricing. Okay. Good. Yes, a couple of more minutes, and we should move on to your pipeline because 1 or 2 absolutely the focus for the near term, midterm, but you do have some -- the pipeline based on the gene editing...

The pipeline involves 3 products, right? First one, it's like 3 carriers of cholesterol in the blood. First one is LDL. The second one is triglyceride-rich lipoproteins. They carry LDL. And the target that we're going after for that is ANGPTL3. This product is in the clinic. It uses the same base editor, the same GalNAc LNP lipid nanoparticle, the proprietary lipid nanoparticle delivery system, same one as in 102. And then the only thing that's different is the guide RNA targets the ANGPTL3 gene rather than the PCSK9 gene. It's dose escalation right now. The major milestone for this product is in the second half of the year, we're guiding to a program update and maybe a data update depending on enrollment. And if it's a data update, it will look similar in terms of scope with what we just shared in April for VERVE-102. The third product is the third -- attacks the third carrier of cholesterol, which is lipoprotein(a). So we're targeting the LPA gene. This product is in preclinical right now. We just announced a development candidate in January, and that got us a milestone from Eli Lilly for about $20 million. And that's a product that's partnered with them as well, and we are making good progress there.

Awesome. You say 201, you may have a data update, but in public, you say this is previous public guidance is a program update. So how likely you will give us the data update because you want to be meaningful just like the 102?

Yes. I think the enrollment is going well. So we'll shoot for a data update.

Okay. Got it. All right. That's good. And then let's talk about the cash runway and then how we're going to support your all the 3 pipeline and additional.

Yes. So we have -- we closed Q1 with about $500 million in cash. This gives us runway to middle of '27. And this runway supports the Phase I for 102, the Phase I for 201 and the Phase II for 102. So really meaningful inflection points ahead within this budget envelope.

And I believe you those 3 pipeline, you will have some relationship with Lilly. Maybe just give us a reminder...

Yes. So once they opt-in, in the second half of the year for 102, they'll pick up 1/3 of the worldwide development costs.

How about the 201 and the 301?

The 201 is a separate decision, separate opt-in decision. Again, once they opt in for that, they'll pick up 1/3 of the worldwide development cost for 201. 301 is a separate relationship, and that's actually -- they're paying for all the research now. So it's fully paid for. We do all the development -- research and development until the end of Phase I, and they're paying for it. And then at the end of Phase I, the product turns over to them, and then they carry it forward from Phase II onward. And then ultimately, we'll receive royalties and milestones.

Got it. Okay. Very good. I think the 30 minutes is up. And then anything else you want to mention?

No, I think we have a super exciting year ahead, and thank you for inviting us.

Excellent. Thank you, everyone, for listening.