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

Good morning. I'm Eric Joseph, senior biotech analyst with JPMorgan. And our next presenting company is Verve Therapeutics. Presenting on behalf of the company is CEO, Sek Kathiresan. There is a Q&A after the presentation. If you have questions, just wait for the microphone and for folks tuning in online, feel free to submit questions via the portal. So with that, Sek thanks for joining us.

Thank you, Eric. Good morning. Really a pleasure to be here to present on behalf of Verve Therapeutics. Verve is looking to transform the care of cardiovascular disease through single-course gene editing medicines. What does that transformation look like? It really looks like a move from chronic care for this chronic disease to once and done, and Verve is uniquely positioned to enable this transformation. And that unique position comes from our know-how. We've been intensely focused on cardiovascular disease and gene editing since our founding in 2018. We picked a set of validated cardiovascular targets validated through human genetics as well as human pharmacology. We've been very flexible on the technology, the editing technology as well as the delivery technology. And in fact, we've actually invented our own GalNAc-LNP delivery technology for our programs. We have 2 of the programs in the clinic, and I'll tell you more about that coming up. And we've generated a fair amount of nonclinical and clinical data as we moved along in our development, and we're well capitalized with runway to mid-2027. So we're really uniquely positioned to enable this transformation from chronic care to once and done for cardiovascular disease. We're developing a pipeline of in vivo gene editing medicines designed to lower cholesterol after a single treatment. Shown here are the targets in the first column, PCSK9, ANGPTL3, Lp(a). Second column shows the indications. You'll see a general pattern of starting with a genetic form of the disease and then expanding out to broader populations for each of the targets. The third column shows the technology the editing technology, so base editing, for example, for the first couple of programs, it also shows the delivery technology, the GalNAc-Lipid nanoparticle that we'll tell you a little bit more about soon. In addition to the base editing approach, we're also have developed our own custom novel editors for a couple of the targets, and those are shown in green. In terms of where we are in development, a couple of the programs are in the clinic, as I said, and several are preclinical. The lead indication for the lead asset is heterozygous familial hypercholesterolemia. This is a severe genetic disease with a significant unmet need for early and durable LDL lowering. This is actually the most common genetic disease in humans and affects about 3 million patients in U.S. and Europe. It really is due to prolonged exposure to high LDL cholesterol, resulting in early heart attacks and strokes. About 50% of untreated men will develop heart disease with this condition before the age of 50. Now here, the diagnosis and treatment is often initiated very late after significant buildup of cholesterol leading to heart artery blockages and that's what's shown on the left. There's an invasive angiogram here that shows the outline of the heart arteries and there's a blockage that's circled, this blockage is the result of decades of exposure to cholesterol and leading to the buildup and blockage. The mean age of diagnosis is typically about 47. And current standard of care is inadequate to durably reduce disease risk and about less than 55 -- 25% of patients of treated patients are actually at LDL goal. So a severe disease, high unmet need, and this is what we're focused on for our lead asset. Now there are 3 cholesterol drivers of atherosclerosis, and that's what's schematized here. LDL or low-density lipoprotein, TRL or triglyceride-rich lipoprotein, and the third is lipoprotein (a). Our pipeline is designed to address each of these carriers of cholesterol. VERVE-102 targeting PCSK9 addresses LDL, VERVE-201 targeting ANGPTL3 addresses LDL and triglyceride-rich lipoproteins, and VERVE-301 targeting Lp(a) addresses lipoprotein (a). Now we often get asked, what's the unmet need here for cholesterol lowering. There are available options right now to lower cholesterol. So what's the unmet need. Now the current treatments do lower cholesterol in a typical patient anywhere from 40% to 60%. But they need to be taken daily and often for decades. So taken lifelong, that requirement for decades of chronic therapy actually leads to poor real-world control of LDL. And that's what's shown on the left. A typical patient whose LDL comes down with initial therapy, but doesn't stay down. There's tremendous oscillation in LDL over the life course leading to poor control of LDL. And some of the statistics on the right illustrate that problem. About 50% of ASCVD patients are not even on a statin medication to lower cholesterol. Only about 2% of eligible ASCVD patients are currently on a PCSK9 inhibitor. And up to 50% of patients discontinue cardiovascular medications within 12 months of initiation. So there's very poor persistence for these medications. Now that poor control leads to high cumulative exposure to LDL, and that's what's shown on the left. And often, this cumulative exposure is described as cholesterol years. So it's really the milligram deciliter cholesterol times the years of exposure to give you a sense of the overall burden of cholesterol. And the years of elevated exposure leads to atherosclerotic cardiovascular events, including fatal heart attack, and that's what's shown on the right. The non-adherence to lipid lowering therapies can increase in event rate by more than 40%. Now what is needed is what we're trying to work on a single treatment that would durably lower LDL and such a treatment has the potential to meaningfully decrease the risk of atherosclerotic cardiovascular disease. So this is really Verve's goal, a onetime treatment with a potential for a lifetime of benefit. Now are we going to be able to get there? Is this really feasible? And with the first version of the PCSK9 product, we call VERVE-101, we were actually able to generate strong proof of concept last year that this whole concept, this whole approach is going to be possible. And this is durability data in humans for VERVE-101 targeting PCSK9 in the first version that we tested in patients. And we're able to demonstrate sustained LDL reduction after a single administration. Shown here on the X-axis time on study out to 18 months. On the Y-axis is percentage LDL lowering. And what you can see in the patient in purple, the LDL came down about 60% 28 days after the onetime intravenous infusion. And then 18 months later, the LDL is still down nearly 60%. And again, providing strong proof of concept, the idea of onetime treatment, a lifetime of benefit. So let me walk you through each of the pipeline programs, starting with PCSK9 and VERVE-102, the next-gen version from -- that we're testing in patients right now. This program, this product can potentially address over 28 million patients in the U.S. and EU. 3 million of those are with the HeFH condition and about 25 million with atherosclerotic cardiovascular disease, not at LDL goal on a statin. So this is a broad potential application. Now here is that product at VERVE-102. It's an investigational in vivo base editing medicine that is delivered by a GalNAc-Lipid nanoparticle and is designed to inactivate the PCSK9 gene. On the left is the schematic of the product. The cargo is mRNA for an adenine base editor. There's guide RNA as well, that directs the editor to the PCSK9 gene and both of those nucleic acids are packaged in a little fat bubble, a lipid nanoparticle. And please note that there is a targeting ligand that's been added to the surface, a GalNAc targeting ligand that further directs this lipid nanoparticle to the liver. Once delivered as an intravenous infusion, so this drug is given as an IV infusion over a couple of hours. Once delivered, the drug gets into liver cells through any of 2 different receptors, either the LDL receptor or the GalNAc receptor. Once inside the cell, the mRNA for the editor is translated to protein. The combination of the adenine base editor protein and the guide make their way into the nucleus, and ultimately make a single spelling change in 1 spot in the genome. A to G at 1 spot in the PCSK9 gene sequence with the intended consequence of turning off the gene. Turning off the gene in the liver cells, shuts down PCSK9 production, the PCSK9 blood level comes down, and ultimately, the LDL-cholesterol level comes down. This product is being tested right now in a trial, a Phase I trial, called Heart-2. And this is testing the safety and tolerability in pharmaco and PD of VERVE-102. Initially, we're testing in patients with heterozygous FH and premature coronary artery disease. Those are the patient populations, and these are patients who require additional LDL lowering despite maximally tolerated oral therapies. The study design is a single ascending dose design with roughly 3 to 9 participants per cohort starting at 0.3 mg per kg and escalating higher and trial endpoints include safety and tolerability, pharmacokinetics as well as changes in blood PCSK9 and LDL levels. This Heart-2 trial is progressing as planned. We're now dosing in the 0.6 mg per kg cohort. Dosing has been completed in 7 participants in the first 2 dose levels as of October 29, 2024. And VERVE-102 has been well tolerated, no serious adverse events and no clinically significant laboratory abnormalities have been observed to date. In Q2 of this year, we expect an initial data release involving 10 to 12 participants across the 3 dose cohorts and with each participant having at least 28 days of follow-up. Again, this is in Q2 of this year. Now one question we get asked is will patients and physicians be open to this approach, a onetime gene editing treatment as a solution for high cholesterol. And here's a survey that we did last quarter involving cardiologists. So over 100 cardiologists all over the United States. And we propose to them a series of options in terms of a future cholesterol lowering landscape and asked for your next 10 patients with either heterozygous FH or ASCVD, what would you prefer as a treatment solution. On the left is the decisions made for HeFH patients, on the right for ASCVD patients. And the options provided were no PCSK9 agent, a PCSK9 monoclonal antibody, and oral PCSK9, which is currently in development, an siRNA targeting PCSK9 or VERVE-102, the onetime treatment that we're developing. And cardiologists preferred VERVE-102 for 40% of their HeFH patients and 20% (sic) [ 19% ] of their ASCVD patients. And these data highlight, I think the archetype of the patient that might be ideal for VERVE-102. These are younger patients with very high LDL cholesterol who require decades of care, decades of LDL lowering. This is likely to be the emerging archetype of patient. And that's what's quoted on the right. These are qualitative results where a cardiologist stated that, "Younger patients could benefit from VERVE-102 for a longer period of time, and for people with very high LDL cholesterol, there's impetus to get levels under control quickly." So these are the kind of patients we think ultimately will take this up. Now in terms of patient surveys, we've also been involved in those. And here's one of those where about 500 patients who all need lifelong therapy for high cholesterol or cardiovascular disease were given 4 options, a daily pill, a onetime gene editing treatment annual injection or twice a month injection, and a full 1/3 of these patients preferred the onetime gene editing option. So there's actually a remarkable openness among the physician community as well as the patient community for this kind of approach. And then to remind you of the existing PCSK9 market, this inhibitor market is growing rapidly. 2024 projections are about $4 billion in sales globally for the 3 products, a 2 monoclonal antibodies as well as the inclisiran or Leqvio, the siRNA targeting PCSK9. And in particular, I want to point your attention to the orange. There's the Leqvio data. Leqvio is growing at over 100% in terms of year-over-year. And there's increasing adoption really illustrates the idea that patients are desire long-lasting treatment to lower LDL. Now despite this $4 billion market, despite the growth, the market actually remains largely untapped. Likely only about 30% to 40% of HeFH patients and less than 5% of eligible ASCVD patients have received a PCSK9 inhibitor in the United States. So there's a lot of room still to grow for this market. Now our product of VERVE-102, we have a close collaboration with Eli Lilly, and they have the ability to opt-in to this program at the end of Phase I. Some of the details of that opt-in are shown here, and we anticipate this opt-in decision to come in the second half of this year. And with an opt-in, Lilly will be contributing 1/3 of worldwide development costs. In return, they'll get 50% of U.S. profits, the other 50% of U.S. is with Verve, and 100% ex-U.S. is Verve. So we retain majority rights here as well as control of development and booking revenues. Here are the anticipated milestones for the PCSK9 program in 2025. We'll have initial data from the Heart-2 clinical trial in the second quarter final data for the dose escalation portion of the Heart-2 clinical trial in the second half, the delivery of an opt-in package to Lilly with the potential for a decision by year-end and then initiation of the Phase II clinical trial in the second half of this year. Let me walk you through in the remaining minutes, VERVE-201 and VERVE-301. VERVE-201 targets ANGPTL3. The product is very similar to 102, same delivery system, same editor, but a different guide. The intention is to turn off the ANGPTL3 gene in the liver, and that will lead to lower LDL and lower triglycerides in the blood. This target has a potential for a broad application across 3 different indications, homozygous FH, a rare orphan disease as well as refractory hypercholesterolemia and severe hypertriglyceridemia. Those are 2 very large indications involving millions of patients. This is preclinical data showing the efficacy of VERVE-201 in a monkey model of homozygous FH, we were able to show that the treatment of these animals with VERVE-201 led to a dramatic reduction in LDL cholesterol as well as triglycerides. This product is currently being tested in PULSE 1 trial. It's a Phase I as well in patients with refractory hypercholesterolemia. The study design is very similar to VERVE-102 with a single ascending dose escalation, and the trial endpoints are also similar to the Heart-2 trial of VERVE-102. We dosed our first patient in this trial in Q4 of last year and anticipate dose escalation -- through dose escalation this year with a program update in the second half of the year. VERVE-301 targets Lp(a). And Lp(a) an LDL-like particle that is a powerful risk factor for cardiovascular disease. About 13 million people in the U.S. have elevated -- U.S. and EU have elevated Lp(a), more than 1/4 of patients with ASCVD have elevated Lp(a), and currently, there are no therapies approved for the treatment of elevated Lp(a). We announced on Monday the nomination of a development candidate for this target in collaboration with Eli Lilly. And this development candidate is designed to durably inactivate the Lp(a) gene in the liver, and we're using a novel in vivo gene editing approach that we've developed internally. And this is delivered by our proprietary GalNAc-LNP. The DC selection here was based on off-target profile that was acceptable, dose response profile as well as the degree of apo(a) reduction in nonhuman primates. For this development candidate, we received a milestone payment or we expect to receive a milestone payment from Eli Lilly. Now we've really been focused on execution in 2024 and have achieved a fair amount that is really enabling a milestone-rich 2025. In 2024, we were able to show proof of concept for potent, durable LDL lowering using the base editing approach for PCSK9 in the liver. The dose escalation of VERVE-102 was started in 2024 using a proprietary GalNAc-LNP delivery technology. And we were able to show across the first 7 patients a very good safety profile and we also dosed the first patient with VERVE-201. These accomplishments in 2024 really allow us to look forward to a set of really key milestones in 2025 that are listed here on the right, including initial Phase Ib data for VERVE-102 in the second quarter, a final data for dose escalation portion of the trial in the second half, delivered the opt-in package to Lilly in the second half, initiation of the Phase II clinical trial in the second half as well as a program update VERVE-201 targeting ANGPTL3 in the second half. Thank you.

We have time for a few questions. And if you have any questions -- if there are any questions from the floor, just raise your hand and we'll bring a mic over to you. But Sek, It'd be great to sort of have you frame the -- set the stage a little bit further into the second quarter readout from the Heart-2 trial? You -- we have certainly guidance on sort of numbers of patients in cohorts you expect to kind of read out on. But from a length of follow-up standpoint, can you talk a little bit sort of the range that could be covered. And from a biomarker standpoint, what are some of the key endpoints you expect to report out on?

Yes. So the initial data release in the second quarter is going to involve 3 dose cohorts, a 0.3 mg per kg, 0.45 mg per kg, and 0.6 mg per kg. And we're guiding to a minimum of 10 to 12 patients across those 3 cohorts. And each patient will have a minimum of 28 days of follow-up. The first patient was dosed in April of last year. So that patient will have almost a year of follow-up. And then the most recent patients will have a minimum of 28 days. And we'll be providing baseline demographics as well as the blood PCSK9 level and the blood LDL level.

Maybe just also learning from the Heart-1 trial. Would you expect to sort of see potentially maximum PCSK9 and LDL reduction at day 28 days or it's more sort of over a longer-term follow-up where you'd have a better sense of the -- or a fuller sense of PD effect?

Actually, the nadir typically for the PCSK9 and LDL is about 28 days. And so we'll have a pretty good sense of the full efficacy profile by day 28.

Great. Maybe just thinking about the market opportunity and also just positioning of a onetime editor. You highlighted the growth trajectory performance of inclisiran thus far. When you talk to physicians or when you survey the physicians, I mean, how do they think about the comparative offering of a onetime editor versus an siRNA approach to knocking down PCSK9. Are these essentially directly competitive approaches? Or do they think about some degree of segmentation as to where either agent might be utilized.

Yes. I think the archetype of patient, though, in terms of initial uptake of this kind of approach would be those who require really decades of LDL lowering. So who are those patients? Well, those are patients who have a genetic form of high cholesterol that they inherited from their parents and from birth, they have very high LDL and require 30, 40, 50 years of care. And patients who may have had a heart attack at a young age, 30s, 40s, who might require, again, decades of LDL lowering. And what's happening right now is despite the availability of other options, most patients are not. Time on treatment is quite low. As I mentioned earlier, 50% of patients are no longer on cardiovascular medication within a year of initiation. So if they're not on the medication, then the cholesterol is not being lowered. And so that's the unmet need right now. And so I think changing that model, the current model, the chronic care model to really a onetime treatment, lifelong -- lifetime of benefit, I think, has a large commercial opportunity.

Do you have a sense of where inclisiran is being utilized currently in terms of either age, history of high cholesterol or even sequencing perhaps potential prior PCS antibody use?

I think it's actually the uptake is growing kind of probably across all of those different categories that you mentioned. And I think the main point is that initially, the inhibitor class started off slow for a variety of reasons, but you can just see the scope of the market by these numbers for -- and I think by the end of this year, there'll be $5 billion in sales. But that $5 billion is really just 20%, 30% of HeFH patients and only a couple of percent of eligible ASCVD patients. So there's a lot of remaining patients that might be appropriate or could be appropriate for our kind of therapy. And so there's a lot of room still to grow.

You are certainly not required and certainly it's not required, and it's also patients are participating in the Heart-2 trial able to be on a background PCSK9 lowering agent, right? I don't know if the sort of -- I don't know if there's a washout in some cases or it's just entirely naive.

No, they cannot be on an existing PCSK9 on because our medicine, of course, inactivates PCSK9. And so if they're on an existing PCSK9, then we're not going to be able to address, assess the efficacy in terms of -- so these are patients who are on maximally tolerated oral therapy.

And have not seen at all in another -- like could patients have been on one and then washed out?

They could have, yes.

Okay. I guess the reason for asking is really twofold. One, whether you would anticipate just a similar knock down, basically, similar tolerability and clinical benefit regardless of prior PCSK9 lowering therapy. And then secondarily, just from a payer perspective, whether -- just how they think about kind of sequencing or positioning of a onetime therapy relative to the other agents that are on the market.

Yes, it's a great question. I think we've showed you some information on physician demand as well as patient demand. But I think an important question that you're asking is, what about payers, how are they going to view this? And I think in general, gene editing, gene therapy, there have been several kind of commercial challenges that have been -- people think about. One of them is that it might be very expensive to manufacture, so high cost of goods. And the second is that it might be very pricey. So millions of dollars of dose, for example. And those are 2 challenges that are often brought forward, and important thing to note is that for VERVE-102, our products, we're actually differentiated. Those 2 challenges, I think, are less relevant. And let me walk you through why. In terms of the cost to manufacture, typically for viral vector gene therapy or ex vivo cell therapy, ex vivo gene editing or cell therapy, it is very expensive to manufacture. But our product is mRNA, packaged in a lipid nanoparticle. This kind of product now we know because of the COVID experience, about 100 micrograms of this kind of material can be made for about $5. So we're going to be giving not 100 micrograms, but probably closer to 50 milligrams intravenous. But even if you multiply up, you're talking low thousands cost of goods. In addition, we're going after very large indications with potentially millions of patients, not a rare disease. And so those 2 factors, the manageable cost of goods as well as the market -- addressable market size actually will give us a fair amount of flexibility in terms of pricing and market access. And so I think we'll be able to ultimately address some of the issues you're talking about in terms of step-throughs and so forth. And I think the market should think about our product much more like other onetime procedures in cardiovascular medicine. And probably the most relevant one would be coronary artery bypass surgery. And this is a onetime procedure permanent intended for lifetime of benefit, a good analogy to our approach. And so think about what the charge is for bypass surgery and how widespread that procedure is and how well it's readily paid for by insurers. So those are -- that's the kind of thing that I think we're thinking about as we move forward.

Yes. Just hold for one second.

A really nice talk. And my question is what's the expected durability of the therapy? And if it's LNP, then is it technically redoseable?

That's a great question. So first, in terms of durability, we have durability data that I just showed you in patients out to 18 months plus right now. In nonhuman primates, we have durability out to 3 years. And in other companies who've done in vivo liver gene editing have durability out to 2-plus years in humans already. So this really looks like truly, it's going to be a one and done. The liver regenerates in primates roughly every 6 to 9 months, and we have durability well beyond that regeneration time. And so we do get asked, well, how is that? Well, how is it durable? -- and given that the liver regenerates. And what's happening is that when we come in and do the editing initially with the intravenous infusion, we're basically editing nearly all hepatocytes and the source of liver regeneration are actually mature hepatocytes. And so they get edited initially when they divide to give forward a new -- to give rise to new hepatocytes, they're carrying forward the edit, and that's why you're getting the durability. In terms of -- your second question was redoseable. Yes, with LNPs, it is redoseable. We've been able to do that in nonhuman primates and shown very good safety profile with the second dose as well as stacking of editing, if needed, in terms of additional efficacy that you get with the second dose. And then I think other companies have actually in humans already shown that redosing with LNP for editing is possible and is tolerated.

Just picking up on that point, not that -- I guess we'll learn more pretty soon in second quarter. But to the extent you see variability in gene editing and by extension, down regulation of PCSK9 and so forth. Does your -- do you have plans in either your existing Phase I or later-stage protocol to evaluate this question of potential for redosing as a means of building in that optionality perhaps in a registration study.

Yes. We don't think we'll need it. I think we're going to be able to get there with a single dose. But if needed, I think we could end up evaluating a multi-dose option, if needed.

Just -- and on 201, just again, just putting a commercial framework around that agent and the opportunity with ANGPTL3. I guess what is the distinct addressable opportunity with an ANGPTL3 lowering agent that is separate from the PCSK9 lowering market?

Yes. So we -- the homozygous FH is our lead indication. That's a rare orphan disease involving about 3,000 patients in U.S. and Europe. And that's a group of patients who benefit from -- specifically from ANGPTL3 in activation. The second indication is refractory hypercholesterolemia. So this is -- these are a group of patients who have LDL that's too high despite being on a statin and a PCSK9 inhibitor. And those patients, we know can benefit from ANGPTL3 in activation because this mechanism of lowering LDL ANGPTL3 in activation is actually additive to PCSK9 inhibition. So those are the 2 groups will be initially evaluating. There's also a third group that I showed, which is patients who have very high triglycerides, so over 500, also called severe hypertriglyceridemia, and that's a group that's available for exploration as well as indication.

In refractory hypercholesterolemia, what's the goal? Or is there a goal with respect to LDL lowering that you want to see, obviously, look at refractory to everything that's sort of available to them. What where would you ultimately want to get them to?

The LDL goal in the U.S. for patients with ASCVD is less than 70.

Okay. Great. And in terms of the update that you plan to provide there, you said later this year, the back half of this year?

Yes, exactly. Second half of '25, we'll be providing a program update for the 201 asset.

Similar scope in terms of the type of update with 102 in terms of multiple dose cohorts, minimum 28-day kind of follow-up or...

Yes. That would be the goal, yes.

Okay. Great. All right. Well, I think we might leave it there for questions. Unless there are any more from the floor. All right. Well, thanks so much, Sek, for the presentation. And thanks, everybody, for joining this session.

Thank you.