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

Thanks everyone, joining us, and welcome to the Goldman Sachs' 40th Annual Care Conference first day. Super excited to have Verve Therapeutics, Sek Kathiresan, CEO, joining us here today. Thank you, Sek.

A real pleasure to be here. Thank you.

So maybe we could start with an overview of your approach in cardiovascular disease and help level set for us, why you believe that onetime gene editing therapy is the right approach here?

So Verve Therapeutics is developing onetime gene editing medicines to treat cardiovascular disease. So think onetime treatment, permanent lowering of blood cholesterol. And I would say there are like 5 reasons as to the why, okay? Number one is that this is the answer to heart attack. So it's pretty clear that if one's LDL cholesterol is really low, lifelong, so let's say, like 50-milligram deciliter lifelong, it's very hard to get a heart attack. So that's probably the main reason to really pursue this strategy. Number two, there's a huge unmet need. As you mentioned, there are a lot of treatment options right now, but time on treatment is really low. Despite the fact that there are several pills, multiple injections, less than 2% of patients with familial hypercholesterolemia are actually had LDL goal, and we can talk about maybe why that's the case. The third is patients actually prefer a onetime functional cure compared to having to take injections for their whole life. The fourth reason is there's a large market opportunity. And just to illustrate that, the PCSK9 medication [ solo ] cholesterol, there are 3 injections right now available. As a class, that class is expected to sell about $3.6 billion annualized based on first quarter sales. Now that $3.6 billion, believe it or not, represents just 2% of eligible patients. So there's a huge market opportunity. And then lastly, I think I want to address a pretty common misconception about our therapy regarding commercial. I think most people think when they think onetime medicines, gene editing medicines, they're thinking millions of dollars of dose. That's clearly not going to be us because we ultimately want to treat millions of patients, and we're going to have the flexibility to do so because we have lots of patients, that's not a rare disease. And second, the cost of goods here could be quite manageable because our drug looks like the COVID vaccine in terms of mRNA packaged in a lipid nanoparticle. And we know that kind of product can be made very cost effectively at scale.

Maybe a follow-up there since you've touched on the commercial opportunity. I guess maybe what is your understanding of the interest from patients to embark on this new type of therapy? It's very different from your orals, from even your PCSK9 RNAi therapies that they may be more familiar with. What is the appetite there?

The appetite is quite high, and I'll give you a couple of analogies in one kind of survey data. I think -- I practice cardiology -- preventive cardiology for 20 years at Mass General Hospital. And patients are quite used to onetime therapies in cardiovascular medicine that are permanent, irreversible, intended for a lifelong benefit. So think bypass surgery, think stent procedures, think renal denervation for blood pressure or radiofrequency ablation procedures for atrial fibrillation. So these are all other onetime procedures. And so I think our medicine is ultimately going to be less a drug, I would say, and more a onetime molecular surgical procedure. So that's really the analogy, I think, we've been trying to talk about, and it's very comfortable for patients and for physicians as well. In terms of the appetite, I think quantitating that, there's a survey done on a couple of thousand patients recently who had high cholesterol or already had a heart attack, required lifelong LDL lowering, and they were given 4 options, a daily pill, twice-a-month injection, twice-a-year injection or a onetime gene editing therapy. And the proportion of patients who chose each one of these was, 1/3 for onetime genetic therapy, okay? About 40% for pills, 4% for twice-a-month injection and 14% for twice-a-year injection. So already at this stage, 1/3 of patients would be open to a onetime functional cure. And this is, I think, a very good indication of the potential appetite.

And do you find that your colleagues, cardiologists, other physicians are as readily excited about this move away from a chronic therapy?

Absolutely because they're very frustrated by that low time on treatment. Theoretically, the current medications can lower LDL anywhere from 40% to 60%. These are the pills or injections. But about 50% of patients 1-year after starting any cardiovascular medication are no longer on them, so think about that, 50% of patients are no longer on them. So their effective LDL lowering is not 40%, 50%, 60%, but 0. And that frustrates physicians. And so the idea that you could have a onetime therapy that lowers LDL for the rest of that patient's life is really a pretty dramatic option.

Got it. We'll just jump into your first clinical data you had last November. As a cardiologist, maybe help us contextualize how meaningful that was to see the first gene-edited therapy here?

Yes. So when we started in 2018 with this concept of won and done for the largest disease affecting the world, people thought, frankly, we were a little bit nuts in terms of whether it would even work. And because there had been no prior examples of in vivo base editing in anything larger than cellular models. So over the 6 years of the company from 2018 to 2024, we basically gotten the product concept to be effective in cells in mice, nonhuman primates. And then this past year, we showed in humans that you can base at it. What I mean by that is make a single base pair change in 1 spot in the PCSK9 gene to turn it off permanently. We can base edit pretty much every liver cell, and as a result, the blood PCSK9 protein made by that gene comes down dramatically, and then the cholesterol comes down dramatically. And so we've treated about 13 patients overall, 7 of them at potentially therapeutic doses, and we saw a range of LDL lowering from about 25% to about 70%. And in that 70% patient provides that really strong proof of concept that it is going to be possible to edit nearly every liver cell in a human being to turn the gene off and have dramatic LDL lowering. Now importantly, the durability of this effect, we already are now seeing out to 9-plus months after the single treatment. And this really is reminiscent of our monkey data, where we have data now almost out to 3 years after the onetime treatment in the nonhuman primates. So this is very strong proof of concept that the base editing approach is going to work. Now at potentially therapeutic doses for this first product, VERVE-101, we picked up some safety signals, specifically transient laboratory abnormality, so a rise in liver function tests, a drop in platelets in 1-patient, that really made us pause this study and really try to understand, can we develop mitigation measures to avoid these transient lab abnormalities. And then meanwhile, we are -- going forward with a second-generation product that uses the same editor and the guide to get the editing to happen, but has a different lipid nanoparticle formulation. So this is called VERVE-102, the trial just started. And we believe this product will solve the laboratory abnormalities we saw with VERVE-101, and we can talk more about that.

Got it. Maybe quickly on the 70% LDL lowering, maybe help put that into context for us relative to other therapies that are out there, what is the bar for new therapies as they come on to the market or as they're being developed to really have a meaningful impact here?

Yes. The bar is really about not only how low you go, which is often what people focus on, the percent reduction, but how long. So because the name of the game here for cholesterol lowering is not only how low, but how long. So we are a differentiating feature, of course, is the duration of therapy, right? Because you want the cholesterol. It's all about the kind of area under the curve. So the existing therapies on the how low are anywhere from 40% to 60% based on the kind of patient population and the specific modality, okay? But the existing therapies, as I mentioned to you, are the average person time on treatment is a few months, maybe 6 months, maybe a year, but the majority of patients are off the medicine at a year. So we're going to want to match, I think, the existing therapies on how low, but how long, that's going to be our key differentiator. So that how low, I think -- so using inclisiran, as an example, which is the siRNA from Novartis and previously developed by The Medicines Company. That medicine in HeFH patients, which is 1-patient population, the first patient population we're going after, this is a genetic form of high cholesterol from birth. In those patients compared to baseline, inclisiran lowers LDL by 40%. In patients, the [ guide ] variety patients, it lowers LDL compared to baseline by 50%. And so those are, I think, reasonable benchmarks for us in terms of how low. But how long, again, is going to be the key differentiator for us.

Got it. But then with the work that you're doing right now to understand the signal that you observed in VER-101, where does that stand? And when can we expect an update?

Yes, I think that work is ongoing. It's nonclinical studies to understand the mechanism by which some of these laboratory abnormalities occur. But most importantly, it's really can we figure out a mitigation measure. Because if we can, then they're very well may be a path forward for 101, where we love the safety signal -- I mean the efficacy signals we saw, we just want to really avert those safety signals.

And what underpins your belief that it is the lipid nanoparticle versus the editor versus the guide?

That's a great question. And it really is very compelling preclinical data that if you take the lipid nanoparticle and put inside cargo that is not capable of editing, so it's basically mRNA plus inactive guide, and you give that construct to animals, you get the same laboratory abnormalities. So really pointing the finger at the delivery system and rather than the cargo, and the delivery system is what's been switched out between 102 and 101.

Okay. Maybe if you don't mind, dig in more there. What really does differentiate the different delivery systems? You have a different enable lipid as you've mentioned. Maybe help us understand it.

Yes. I think this is another large misconception in the field. When people say, "Oh, use a lipid nanoparticle, there's no such thing as a single lipid nanoparticle." it's like -- it's really different chemical matter that's put together to get to that spherical shell. The lipid nanoparticle typically has 4 components, and each of those can be different across nanoparticles. So the 4 components are, an ionizable lipid, a PEG lipid, a phospholipid and cholesterol. Now the phospholipid and cholesterol are generic and pretty much similar across LNPs. The 2 differentiating factors really are the ionizable lipid and the PEG lipid. And the ionizable lipid is probably the most critical in terms of determining the potency and the safety profile. So this is a chemical structure, ionizable lipid, and for VERVE-101, we in-license ionizable lipid from a company called Acuitas Therapeutics. And then the PEG lipid was also licensed in from Acuitas. So that's our 101. For 102, the PEG lipid -- the ionizable lipid is different, the PEG lipid is different. The ionizable lipid is licensed from Novartis. And the PEG lipid is a commercially available PEG lipid called PEG-DMG 2000. So those are 2 key differences 101 and 102. There's also one additional difference that was we added a targeting ligand to 102, a GalNac carbohydrate that is anchored to the surface of the lipid nanoparticle, remember, the lipid nanoparticle you have the cargo in the middle, the mRNA and the guide, and then those are then negatively charged. And then this little fat bubble, the lipid nanoparticle envelops the cargo. And we've anchored to that little spherical bubble a carbohydrate that comes out on to the surface. And that carbohydrate is GalNAc. It's a proprietary GalNAc. There are other GalNAc out there initially developed by Alnylam, for example, that's conjugated to nucleic acids. But this is our own proprietary GalNAc. So the GalNAC LNP is really the -- is our 102 with those components.

And when you think about your preclinical data sets that you've had for VERVE-101, and you've developed for VERVE-102, how do they compare? And I guess maybe what is the level of confidence that, that gives you as you think about this Heart-2 study?

Yes. So there are 2 items that would give us a lot of confidence regarding 102. First is the ionizable lipid that's used, that's being used, that's licensed in from Novartis has already been tested in third-party clinical trials over 100 patients dosed. And that ionizable lipid has been well tolerated and with good efficacy. So that human data gives us confidence. And second, in our own preclinical data with 102, we see that -- with 101, we saw the ALT changes and the platelet drops at very high doses, doses higher than the no observed adverse event limit for 101. For 102, we don't see any pronounced platelet drops at any dose that we give. And the LFT changes are much milder. So the preclinical -- our own preclinical data in nonhuman primates gives us confidence as well as that human data that I mentioned.

Got it. And now with the initiation of Heart-2, just help us think through what the trial design looks like? Have you disclosed what doses you're looking at there? How comparable are those doses to what you were looking at with 101?

They're comparable doses, and we haven't disclosed the exact doses in terms of public guidance. The study design is basically a single ascending dose design, a few patients at each dose level, roughly 3 to 9. It's flexible, adaptive design. And the goal is to identify the dose where we get good efficacy and of course, without a safety signals. In terms of the patient population we're studying, it's a little bit different than 101. It's expanded. And so we have the heterozygous FH group, which is the patients with the genetic form of high cholesterol and from early in life, and about 3 million patients in U.S. and Europe with HeFH, heterozygous familial hypercholesterolemia. We've also added a group called premature coronary artery disease. So this is just a fancy term for anybody who's young, who's had a heart attack. And the age cutoff we are using is men less than 50, women less than 60 with a heart attack. This is actually a large -- this is about 20% of all heart attacks in the U.S. and Europe. So we've got -- I mean those 2 groups are being studied. The reason we chose those 2 groups is, again, going back to our key differentiator, which is lifelong LDL lowering. So we wondered who are the people that need not only -- how low versus how long, who needs deep LDL lowering for decades. And so if you've got a heart attack at 35 or 40, you're looking at like 30 or 40 years of daily pills. That's just not happening right now. So I think those patients would be particularly benefit from a onetime therapy that has durable effect as well as the patients who have HeFH.

And when can we expect first data here?

We're guiding to data in 2025. And as the year goes on, we hope to be able to narrow that guidance in terms of further within '25.

And are you still committed to -- I mean I guess, maybe evaluating VERVE-102 against VERVE-101? How should we think about your strategy to bring 1-asset forward?

Yes. If you recall when we chatted last year, we explicitly laid out the strategy of having 2 product candidates that differed only in the delivery system because we knew that delivery was one of the key risks for the whole field. There's only been one example really before us, Intellia, that had taken from preclinical data to humans for in vivo gene editing in terms of delivery. So we knew that delivery was a risk. So we had 2 product candidates. Our goal was to evaluate both in the clinic, pick 1 to go forward to Phase II in 2025. And that time line is still entirely on track. Nothing's changed there. What we want to see now is the 102 data, but with 101, the main thing would be, can we develop a mitigation measure that would avert the laboratory abnormalities. If we can, there very well may be a path forward for 101.

What types of mitigation strategies are on the table here?

I mean I think that the typical ones you think about for this kind of thing would be concomitant medications that might dampen the AEs. The other would be some sort of -- we always call our medicine single-course treatment. And what is meant by that is, you could imagine taking the required dose and splitting it into 2 doses and being given, let's say, 30 days apart. And that's often a strategy to keep the efficacy, but take away the safety profile, particularly the safety profile is driven by, let's say, Cmax or even area under the curve. Because when you split the dose and divide it in half, you're going to have less given during that time and hopefully less safety signals. Now we've already shown in preclinical models that you can take -- you can split the dose and give it 30 days apart in nonhuman primates, and you actually get stacking of efficacy after the second dose in terms of editing in the liver, but you don't actually have any more safety signals from either dose. So that strategy would be another option.

And would you, I guess, maybe look to evaluate that strategy of the stacking or the multi-dose before you make a decision on VERVE-102?

I don't think so. VERVE-102 has the profile that we're looking for, let's say, the same efficacy as 101, but no safety signals and that, that might do the trick just to move forward directly from Heart-2 trial.

Got it. And with VERVE-102, remind us that is being conducted ex U.S., are there plans to file an IND here in the U.S.? Or where does that stand?

Yes. I think the key thing for us is that with 101, we got an IND cleared. That IND is -- we now know what it takes in terms of the FDA for in vivo base editing, the set of requirements. And so we're going to kind of keep that in our back pocket. And basically for 102, it's really about where can you most efficiently enroll, and then take that data and move it forward in terms of a global regulatory strategy. So for IND for 102, current plans are really with Phase II.

And what does that Phase II trial look like?

The Phase II -- so the key thing between Phase I and Phase II is adding a control group. So Phase I is there is -- it's an open-label trial without a control group. So everybody is getting treated. And that's appropriate for a SAD design. But I think for Phase II, we're going to want to have a group that gets kind of placebo infusion. And besides that, it will probably be 1 or 2 doses. So the goal, of course, is pick a -- get an effective and safe dose for a larger Phase IIIs. And I think the inclisiran development program is a reasonable benchmark for what you're going to expect from us from Phase I, Phase II and Phase III for HeFH. Their program -- remember, that modality, siRNA for cholesterol, was brand new just a few years ago and had some of the same concerns or questions that people are asking now about the new treatment modality. There are already pills available, there's already antibodies, do you need something else and so forth. And -- but you saw that they developed with a Phase I and Phase II with the control group. And then their Phase III for heterozygous FH was about 500 people with half treated, half controlled.

And then what is your latest thinking on the need for a cardiovascular outcomes trial?

Yes. For heterozygous FH, there's never been a cardiovascular outcomes trial required or completed. I think all approvals to date for the pills, the antibodies, the siRNA for cholesterol have come based on LDL as the endpoint. That's our expectation as well for this modality. Now I think we may end up pursuing a cardiovascular outcomes trial for -- more for market adoption and commercial, but we don't think it will be required for registration.

Got it. We've also talked about in the past, Verve's goal of going after 3 different pillars of lipoprotein risk. Remind us maybe the rationale behind that? What is the latest thinking on maybe what is the best or the most appropriate target to go after to really be able to reduce that risk, and think about the [indiscernible] development?

Yes. So I mentioned the answer to heart attack is getting the cholesterol as low as possible for as long as possible. I'm talking like 50-milligram deciliter lifelong. If that's the case, very hard to get a heart attack. Cholesterol is carried in any of 3 different particles. One is LDL, low-density lipoprotein, and that's called low-density lipoprotein cholesterol. There's a second set of particles called remnant particles, also called triglyceride-rich lipoproteins. And the cholesterol carried in those particles is called remnant cholesterol. The third particle is called lipoprotein (a) and that's lipoprotein (a) cholesterol. So we want to have a product ultimately that attacks each of these 3 carriers of cholesterol in the blood. Our PCSK9 target it attacks LDL. Our [indiscernible] program attacks LDL and that remnant cholesterol -- remnant particles. And then the LPA program attacks the third group of lipoprotein (a). Overall PCSK9 and LDL is the dominant factor for everybody. But in some patients, there's remnant can be a problem as well, so that's why we have that second option. And then in a smaller fraction of patients, LPA is the main driver. And so we have that third option.

That's a great segue to 201. Maybe give us an update there on where you stand? And the -- you've talked here about the rationale for targeting ANGPTL3, but any more details you can provide?

Yes. I think the ANGPTL3 program are set up in terms of the next 18 months -- 12 to 18 months. It's very -- our whole platform is very modular; our pipeline is modular. Once we derisk the delivery system, you can just switch out the cargo and then you have a series of products. So the GalNAc LNP is a delivery system that's being derisked right now. Right now, it's carrying PCSK9, guide RNA and the mRNA for the base editor. The second product is the same GalNAc LNP, and the same editor, base editor, but a different guide, the guide now targets ANGPTL3. ANGPTL3, if you turn that gene off, you lower cholesterol in a way that's independent of PCSK9. So it's additive in effect to PCSK9. And it works in a group of patients called homozygous FH, which is a rare orphan disease. So this is our only indication in terms of our pipeline that is a rare orphan disease. And that has particular advantages here because the registration here for an antibody targeting ANGPTL3 would occurred with about 60 patients of data. So we think we can develop the 201 program into a functional cure for the LDL component of the homozygous FH patients with 201 with a much smaller study, possibly as low as 50, 60 patients. And this might be our first product to market, actually. Now on top of the homozygous FH patient population, this product could be added to another group called refractory hypercholesterolemia. These are patients who have high LDL despite statin plus PCSK9, so this could be the second -- the next group. And that's a pretty large group of patients, about 7% of all patients with heart disease, coronary heart disease. So that's our second product. The third product, I think we can talk about now maybe is lipoprotein (a). And here, this is a partnership with Lilly. And I think this gives me a chance to kind of talk a little bit about that relationship. So for this product, LPA, we are doing the research, Lilly is paying for all the research. And we take it through Phase I and then the program transferred over to them. And then at that point, we get royalties and milestones [indiscernible], but we can also opt in for a profit share. So that's the LPA relationship with Lilly. We do have a relationship with Lilly for our first 2 programs as well, ANGPTL3 they could potentially be a partner. But there for those 2 [indiscernible]. Okay, that's what Lilly holds. What I mean by that is [indiscernible] both of them. But at the end of Phase I, they have the ability to opt in, then they pay for 1/3 of worldwide development costs. In return, they get 50% of U.S. profits. The other 50% of U.S. is owned by Verve and 100% of ex U.S. is owned by Verve. And we control development, and we book revenues for those products. So Lilly owns minority rights for PCSK9 and ANGPTL3. Now we're super excited to have Lilly as a potential partner for all 3 of these programs because this is really cardiovascular disease, and there's a -- they have a lot of expertise in development in cardiovascular disease and that they really are aligned with us that the next big thing to do in cardiovascular disease is not go after new targets, but rather pick the existing targets of high conviction and develop a new treatment modality to won and done option against each of those. So that's what's happening with us.

So when you think about your Lilly partnership, I mean that's a great example where the structure of that partnership or the type of work is different across the different programs. How do you think about the strategy when you're contemplating how best to move forward with a partner, what goes into that decision-making process?

Well, I think the Lilly and the Vertex, those are the 2 major partnerships that we have, to give you a sense of how we choose partners. I think Eli Lilly is probably no better company in the world right now to work with for cardiometabolic disease for a range of reasons that people are familiar with. Now Vertex, that's a collaboration where we're focused on not on cardiovascular disease. That's actually the only product in our pipeline that is liver disease. And we chose to work with them because they have deep expertise in this disease. They're really a wonderful partner. And that structure is very much like the LPA structure, where they're paying for all the research now through Phase I, and then we have the ability to opt in, again. We transfer over to them after the end of Phase I, and then we can opt in for a profit share if we choose to do so. So different structures based on the company, based on the targets, based on what we can bring to the table versus what the other party can bring to the table.

And then we touched on a little here. You mentioned base editing, but there's obviously a number of other strategies here within genetic and genomic medicine and [indiscernible]. How do you think about the capacity of your platform [indiscernible]?

[indiscernible] so we're really focused on generating products specifically in cardiovascular disease. And so we're very technology flexible, and you can see that in our pipeline. We are open to different editing technologies. We're open to different delivery technologies. We simply want to make the best product possible. In terms of editing, we're using base editing for our first couple of products. But you can see from [indiscernible], we're developing our own bespoke editor for the [indiscernible] as well as the program with Vertex. So it really like, I think the team that we've built and our focus [indiscernible] to develop, to address unmet needs.

Maybe in the last couple of minutes here, as you look forward over the next 12 to 18 months, what should investors be sure to take note of?

Well, I think it's an incredibly exciting time. We're on the cusp of derisking the delivery system. And as I mentioned, really spring-loaded for success in terms of the additional cargo can be switched out. And we have a robust pipeline to address atherosclerotic cardiovascular disease in a very systematic way. LDL cholesterol, remnant cholesterol, lipoprotein (a) cholesterol. And these are huge markets. There's about 50 million people with -- in U.S. and Europe with ASCVD, and there's a couple of million people with the heterozygous FH. And so -- and as I mentioned, there's a huge unmet need despite the fact that there are available treatment options, and I'll come back to that, there is the couple of misconceptions. One is this idea that the treatment is millions of dollars of dose and how we'll end up, people end up paying for it and so forth. And I don't think we're going to be that. We don't have to be that because I think our products will ultimately look more like onetime medical procedures in cardiovascular disease that are paid for every day right now by Medicare, by commercial payers and so forth. So there's a path already. So I think that there's -- it's an exciting next 12 to 18 months for us as we move through the SAD phase and derisk the delivery system.

Great. Maybe one last question. Just remind us on your cash runway. Where does that get you to?

Yes. So we ended Q1 with about $606 million. This gets us to late '26, if not into early '27. And I think that runway gets us Phase I data for 102, Phase I data for 201, and then further progress on LPA. We received our first milestone payment from Lilly for LPA product that reflects our progress. And so we'll continue to make progress there. And so those are the key inflection points, I think, within this budget envelope.

Awesome. Well, with that, Sek, thank you so much for joining us. Thank you, everyone.

Thank you.