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

Great. Okay. So I'm Eric Joseph, Senior Biotech Analyst with JPMorgan. Our next presenting company is Verve Therapeutics, and it's my pleasure to welcome Sekar Kathiresan, CEO, to take us through the story. There is a Q&A session after the presentation. There will be mics circulated around the room. And for those tuning in online, feel free to submit a question via the portal and I'll work those in where appropriate. So with that, Sekar, thanks for your time.

Okay. Good afternoon. Thank you to the JPM team and Eric for the opportunity to present our story today. My name is Sekar Kathiresan. Prior to founding and leading Verve, I spent 20 years as a cardiologist at Mass General Hospital practicing preventive cardiology and a professor at Harvard Medical School, researching the genetic basis of cardiovascular disease. At Verve, we are looking to transform the care of cardiovascular disease and move it from chronic care to once and done. We've assembled a world-class team that has innovated on delivery. We've advanced the first cardiovascular disease base editor from concept to clinic that's VERVE-101, which is in a global Phase Ib heart-1 clinical trial currently. We've expanded our portfolio through strategic partnerships, and we're well capitalized with a runway to fuel operations into the second half of 2025. The problem we're trying to tackle, atherosclerotic cardiovascular disease, or ASCVD, remains the leading cause of death worldwide despite available treatments. Hundreds of millions of patients worldwide, about 800,000 heart attacks per year in the United States, and one person dies every 34 seconds from cardiovascular disease in the U.S. Now what causes ASCVD? High-cumulative lifelong exposure to blood cholesterol clogs the heart arteries leading to ASCVD. The cholesterol can be carried in any of 3 lipoproteins shown on the left, LDL or low-density lipoprotein, TRL or triglyceride-rich lipoprotein. Sorry. And Lp(a) or Lp(a). What's the solution to ASCVD? Okay. So what's the solution to ASCVD? It's to keep the blood cholesterol as low as possible for as long as possible. We're probably all meant to live with an LDL-cholesterol less than 70, lifelong. Now how good are we at getting that LDL down and keeping it down currently? Well, it turns out not very good. Only about 50% of patients, ASCVD patients in the United States are even on a statin, only about 27% of ASCVD patients in the U.S. are at LDL-cholesterol goal. The current chronic care model to lower LDL-cholesterol is broken. And that model involves daily pills and/or intermittent injections for often decades. And that model places a heavy burden on patients, providers and the health care system, requiring rigorous patient adherence, extensive health care infrastructure and regular health care access. Now let me walk you through that chronic care model and the challenges associated with it for a patient with heterozygous familial hypercholesterolemia, or HeFH. This is patient JV. She was diagnosed at age 4 with very high LDL-cholesterol because her father developed heart disease at a young age. During her 20s and 30s, her LDL remained very high, untreated. At age 44, she presented to the emergency room with chest pain, was diagnosed with a coronary blockage and treated with a stent. She was put on oral medications to lower cholesterol and unable to access a PCSK9 inhibitor, her LDL sits today at 130-milligram deciliter, well above the goal of LDL less than 70. She is a considerable risk for progression, for disease progression. And unfortunately, her situation is not unique and illustrates the need to fundamentally change the way this disease is cared for and move it from chronic care to once and done. At Verve, we're advancing a pipeline of single-course, in vivo gene editing programs. And let me walk you through that pipeline. The first 3 programs address the 3 pillars of lipoprotein risk. LDL, TRL and lipoprotein (a). The first program, VERVE-101, targets the gene PCSK9 and the first indication is heterozygous familial hypercholesterolemia. And the editing technology we're using is a base editor and that program, as I said, is currently in the clinic. The second program, VERVE-201, targets ANGPTL3. The initial indication is homozygous familial hypercholesterolemia and again, base editor as a technology. The third program targets Lp(a), and I'll be describing that program a little bit in a few minutes. And here, we're developing a bespoke editor, a novel editor specific to this target. A couple of other points about our pipeline. They're all in vivo liver gene editing medicines delivered with LNP delivery technology. You can see that we're technology flexible, sometimes using a base editor and other times, developing our own editors. And lastly, we've opportunistically gone beyond atherosclerotic cardiovascular disease for the last program, and that's a straight up liver disease. That's our collaboration with Vertex. Let me tell you about VERVE-101 targeting PCSK9. This is being tested right now in a Phase Ib clinical trial. The initial indication is HeFH. This is a high-risk condition with significant unmet need. Globally, about 97% of patients with HeFH are not at LDL goal. And in this patient population, medicines targeting PCSK9 are approved to lower LDL-cholesterol. So the target is well validated. Now VERVE-101 is designed to permanently turn off the PCSK9 gene in the liver. It's delivered as a onetime intravenous infusion that's shown on the left. On the bottom left is the drug product. It's an mRNA for the editor, a guide RNA that tells the editor where to go in the genome to make the edit. And both of those nucleic acids are packaged in a lipid nanoparticle. Once inside the bloodstream, the drug product makes its way to the liver into liver cells, makes a single spelling change in the DNA sequence of the PCSK9 gene and the consequence is switching off the gene, leading to reduction in plasma PCSK9 protein level and blood LDL-cholesterol level. These are the data for VERVE-101 in nonhuman primates. Shown on the left are the reductions in blood PCSK9 level and shown on the right are the reductions in blood LDL-cholesterol level. On the x-axis is days post infusion, on the y-axis is the degree of reduction from baseline. On the left, you can see that about 2 weeks after the onetime intravenous infusion, the blood PCSK9 protein level comes down by about 90%. And then a year later, the blood PCSK9 level is still down 90%. On the right, you can see the LDL-cholesterol comes down by about 70%, and a year later, the LDL-cholesterol is still down 70%. Currently, VERVE-101 is being tested in the heart-1 trial, a single ascending dose design, 4 dose levels, roughly 3 to 6 patients at each dose level. We've taken a global regulatory strategy. We've gotten regulatory clearances in New Zealand and the U.K., and we're working to resolve an IND application hold and start the trial in the U.S. as well. Recruitment is ongoing in New Zealand and the U.K., and we're enrolling high-risk HeFH patients. These are patients who have established ASCVD and LDL not at goal. We're expecting initial data for the SAD portion of the trial in the second half of 2023. And that initial data will include safety parameters, blood PCSK9 level and blood LDL-cholesterol level. This is the stepwise clinical development strategy for VERVE-101, starting with HeFH, the current trial of Phase Ib in high-risk HeFH. After this, we expect to move on to a Phase II in all of HeFH and then a pivotal Phase III in HeFH with the LDL-cholesterol as the approval endpoint. Ultimately, we expect to expand beyond this indication to garden variety atherosclerotic cardiovascular disease, an even broader patient population. Now lowering LDL-cholesterol by targeting PCSK9 remains a large unmet need, and our first program is addressing that unmet need. Let me move now to the second program, VERVE-201, targeting ANGPTL3. Here, first patient dosing is anticipated in 2024. ANGPTL3 is a compelling target to lower LDL-cholesterol. Humans who lack this protein, who are deficient in ANGPTL3 have very low lipid levels, are resistant to ASCVD and are healthy. They're free of adverse events or effects. We'll be pursuing the ANGPTL3 product in 2 ASCVD indications with a high unmet medical need. The first is homozygous familial hypercholesterolemia or HoFH. This is a rare orphan disease where the LDL cholesterols are extremely high, over 500-milligram deciliter in a lot of patients. The second indication is a larger indication, refractory hypercholesterolemia. And that's defined as ASCVD, not an LDL goal on oral medications plus a PCSK9 inhibitor. For HoFH, again, a severe orphan disease on the left is the unmet need. About half of these patients don't get to LDL goal even on 5 lipid-lowering medications. And in this patient population, a medicine targeting ANGPTL3, a monoclonal antibody has already been approved to lower LDL-cholesterol. In the refractory hypercholesterolemia patients, about 13% of ASCVD patients fall into this category. This is a group of ASCVD patients not at LDL goal despite statin and a PCSK9 inhibitor. And in this patient population, again, ANGPTL3 inhibition has been proven to work. Now VERVE-201 is designed to permanently turn off the ANGPTL3 gene with base editing to durably lower LDL-cholesterol and triglyceride-rich lipoproteins. A onetime intravenous infusion makes its way to deliver a single spelling change in the sequence of the ANGPTL3 gene, and the consequence is to switch off the ANGPTL3 gene leading to potent and durable reductions of LDL as well as triglycerides. This is the preclinical data for the ANGPTL3 program. Again, nonhuman primates, a single intravenous infusion of the drug product. You can see that a couple of weeks after the infusion, the plasma ANGPTL3 protein comes down by about 96% and stays down for 2 years now on the x-axis. So we've been able to switch off this cholesterol-raising gene for good. We're currently executing on this program with a lead candidate that we announced last year. We're currently conducting this year studies to enable regulatory filings, and we expect to dose our first patient with VERVE-201 in 2024. Now for this program, we had to overcome a delivery challenge. Specifically, homozygous FH patients lack the LDL receptor. In that setting, standard lipid nanoparticles don't work. So if we want to edit the ANGPTL3 gene in HoFH patients, we had to come up with a different delivery mechanism. And that's what we did, a novel liver delivery platform, a GalNAc-LNP. Shown here on the left is an LNP decorated with a GalNAc-targeting ligand. On the right, you can see that this GalNAc-LNP will bind to the ASGPR receptor on the surface of liver cells, enabling delivery to HoFH patients. Now we think that this delivery system has the potential to become a best-in-class for delivery of genetic medicines to the liver. We've tested the GalNAc-LNP for a range of targets, including ANGPTL3 as well as PCSK9. And in nonhuman primates, GalNAc-LNP delivery leads to effective in vivo liver editing for both these targets and reductions in the respective plasma proteins shown on the left for ANGPTL3 and on the right for PCSK9. Let me move now to targeting the third pillar of lipoprotein risk, Lp(a). A little bit of background on Lp(a). High blood levels of lipoprotein(a) contribute to the risk of ASCVD. Lp(a) is basically an LDL particle with another protein attached to it called apo(a). This is a liver-derived lipoprotein. It circulates in the blood stream, and it's associated with higher risk for ASCVD endpoints, including myocardial infarction and ischemic stroke. High Lp(a) is a large addressable market. Shown on the left is the distribution of the blood Lp(a) in patients with atherosclerotic cardiovascular disease. About 20% of ASCVD patients have an Lp(a) level greater than 150 nanomoles per liter, a level that increases risk for atherosclerotic cardiovascular disease. Now these patients that have a high Lp(a) are distinct from those who have high LDL. There's actually low correlation between the blood LDL-cholesterol and the blood lipoprotein (a). Now why a once-and-done gene editing medicine for Lp(a)? Well, it turns out, like PCSK9 and like ANGPTL3, humans with genetic Lp(a) deficiency are resistant to heart attack, and there's no signal for adverse events. The blood level of Lp(a) is almost entirely determined by inheritance and lifestyle factors and statins have minimal to no impact on Lp(a). So this makes it a great target for the genetic medicine like the one we're developing. We have research efforts ongoing right now to develop a bespoke gene editor tailored to target Lp(a). Now Verve's pipeline of gene editing programs addresses distinct ASCVD subsets. If you look at VERVE-101 targeting PCSK9, you have HeFH as an indication as well as ASCVD patients not at LDL goal on a statin. VERVE-201, targeting ANGPTL3 can address HoFH patients as well as patients with refractory hypercholesterolemia. And finally, the Lp(a) program can address ASCVD patients with high Lp(a). So if you look across these 5 indications, we're talking about millions of patients who could ultimately be helped by the medicines we're developing. At Verve, we're focused on our mission to transform the treatment of cardiovascular disease from chronic management to once-and-done medicines. Verve was founded in 2018. In 2020, we provided proof of concept for in vivo liver base editing in nonhuman primates. In 2022, we treated our first patient with VERVE-101, a first-in-class medicine. And this year, we're expecting initial data from VERVE-101 -- for VERVE-101 from the heart-1 trial. We're focused and we're well capitalized to continue to execute. Now here is the current model -- care model for a typical patient with HeFH, very high LDL-cholesterol, heart attack shown here at age 44, gets put on treatment. The LDL comes down but doesn't usually stay down. There's oscillation in the LDL over the life course because of the issues like adherence or access. And that lack of control, LDL control leads to recurrent heart problems like a stent or bypass surgery or even a fatal heart attack. Now imagine if we could replace this picture with this picture, a onetime therapy, potent and durable LDL lowering. If we can make this happen, we can fundamentally change the way this disease is treated. Now you may be wondering why wait until somebody has already had a heart attack. Well, ultimately, a medicine like VERVE-101 may be useful to prevent a heart attack in the first place. And at Verve, this is our bold mission to protect the world from cardiovascular disease. Thank you.

All right. Thanks, Sekar. I guess I can kick it off with questions as folks prepare theirs. Maybe just starting with just sort of the -- sort of the heart-1 study in heterozygous FH patients. I'm just wondering how should we be thinking about sort of the variability of LDL-C levels among these patients. And ultimately, really, what threshold in LDL-lowering are you hoping to achieve with VERVE-101 in the Phase Ib study?

So this is a Phase Ib study. So I think the initial goal really is about safety of our medicine. Is VERVE-101 well tolerated across the 4 doses? Now we'll also be measuring, of course, the blood PCSK9 and blood LDL level, and we'll look to see what the efficacy is like as well. But really, the initial SAD phase is about safety. That's really the primary goal.

Okay. Okay. From your nonclinical studies, is it sort of possible to make a comparison of the level of LDL-C reduction that you're getting with VERVE-101 versus some of the existing approved products, either with the anti-PCSK9 antibodies or siRNA? Are you able to sort of compare sort of the nadir levels of LDL reduction that you're able to...

Yes. Based on our preclinical studies as well as the human studies with inclisiran and siRNA targeting PCSK9, I think we do have a pretty good understanding for any given degree of reduction in plasma PCSK9, what degree of LDL reduction are you going to get. So you saw the data that I just showed. In nonhuman primates for a 90% reduction in plasma PCSK9, you've got about a 70% LDL reduction. And I think the question is with our drug product with VERVE-101, what degree of editing, what degree of plasma PCSK9 reduction are we going to get across the 4 dose levels. And that's really the experiment that's being conducted right now.

As you present the data looking at sort of relative reduction, is that -- I'm wondering if that's sort of the most appropriate way to sort of think about the level of reduction you might achieve in patients. I guess, ultimately, you do -- you care about absolute reduction or at least getting to an absolute sort of threshold to be clinically meaningful. Is it -- can you extrapolate from the NHP data, the absolute reduction in LDL that you're achieving as to sort of how it might inform ultimately the dose that would be effective in patients?

Yes. No, actually, the relative reduction from their baseline is probably one of the best metrics to understand the clinical effect on heart attack. And we do have a good sense of that for any given degree reduction of plasma PCSK9, what degree of LDL are you going to -- reduction are you going to get? And then we know what that degree of LDL reduction is going to translate in terms of heart attack risk.

Okay. So I guess, suppose one point of -- one thing that we're all sort of seeking to better understand in the genome therapy space is really the regulatory block and tackling that needs to be done with your program -- any of these programs really and you're currently in the midst of a clinical hold with VERVE-101 here in the U.S. Can you just sort of talk about what sort of needs to be -- what additional data analysis the agency is looking for and how you expect to sort of resolve or see that IND hold result?

Yes. So we -- as we -- as I mentioned, have clearances in New Zealand and U.K. Those enrollment is ongoing there. And we pursued a global regulatory strategy that had kind of 2 tracks. One is to be able to efficiently enroll patients and really understand the safety and efficacy of VERVE-101 and not be overly dependent on any one geography. The second was to engage with the U.S. FDA and understand what their bar was going to be for this kind of product. Now it turns out, we're the first in front of -- I believe we're the first in front of the U.S. FDA with this kind of product. So LNP delivered in vivo liver gene editing. And so we are working out with them in real time, really what the standards are going to be, what the regulatory expectations are going to be. And we put together a comprehensive data package and submitted that in October. They have some additional questions. As you know, after a 30-day period of review, if they have additional questions, their only recourse is to place the application on hold, and that's where we are right now. We're working with them to really define the answers to the questions that they have and align and then conduct the experiments that are needed. We put out a disclosure about a month ago that kind of outlined broadly what the major areas were. And they really are preclinical, 3 major areas. One has to do with thinking about potential potency differences between human and nonhuman species in terms of the drug product. The second has to do with looking at editing, a potential editing or rule out potential editing of sperm or egg cells. And then lastly, has to do with off-target analyses and the cell types that need to be looked at beyond the liver. And so these are the 3 sets of questions that we're really dialoguing with them about.

Okay. All right. I mean certainly, the outcome from all of those -- that additional work ought to be beneficial for the follow-on programs, particularly 201, the ANGPTL3. Is that a fair sort of assumption? I guess, having -- going through this process, do you expect the IND submission -- review of the IND submission for 201 to be relatively smooth?

Absolutely. I think we're learning a lot in terms of what the regulatory expectations are going to be in terms of the FDA, and this is going to help us a great deal for our future programs. And this is the reason we actually chose to engage with the FDA early in development. I think that different companies have made different choices as to when to engage with the FDA with these kind of products. We made an explicit decision to engage early because we wanted to understand what the regulatory expectations were going to be. In the meantime, as I said, as that's happening, we're simultaneously getting clinical data and that time line to clinical data for VERVE-101 when the heart-1 trial is not dependent on the FDA process.

Okay.

Very impressive. You have some estimates on patient population in the U.S.? And do you have any global estimates, any other concentration in the geographies?

Yes. As you know, cardiovascular disease -- atherosclerotic cardiovascular disease is the leading cause of death worldwide, and it's really an epidemic now in developing world like China and India. And so I think the medicines we're developing -- we're developing are going to be relevant globally in addition to U.S., EU. And so the estimates in terms of the numbers we have here are even greater abroad in terms of the total number of individuals at risk or with disease. And so we're excited, ultimately to just have this be a medicine in these populations, but also worldwide. And I should mention one more thing. The one-and-done concept may be particularly attractive in the developing world where there's not this -- typically, this kind of infrastructure for regular health care over time. And rather it's often episodic, people only get the care when they get sick. And so somebody comes in with a heart attack in China or India, they may end up getting treated with a onetime procedure to, let's say, a stent to open the cloud artery, but you could imagine maybe shortly thereafter, they get a onetime treatment to permanently lower their LDL-cholesterol and be done with that LDL care for the rest of their life. So that is an attractive potential model outside of the U.S. as well.

Can you say more about the gene editing approach you're taking with the Lp(a) program? I guess there are a couple of different -- I presume it's an alternative to base editing that you're pursuing. I guess can you elaborate, maybe shed a little bit of light on the type of perhaps endonuclease that your -- or nucleases basically that you're looking to adapt to this target? Are there several that you're evaluating? And then sort of when -- how far out from development candidate selection are you?

Yes. So for this target, our approach is similar to the way we approached PCSK9 or ANGPTL3. So we're very technology flexible, product-focused, technology flexible. So we -- with every any target, we basically ask, okay, what are the different set of editing options that might be available and directly compare in experiments, in cells, in preclinical models. And we've done that for Lp(a). We've evaluated standard Cas9. We've evaluated base editing and find that we really need to look elsewhere for that target. And right now, the gene editing space, as you know, is evolving pretty rapidly. And if you think about an editing system, there are several components. There is, for lack of a better term, kind of the GPS localization component of the editor. There is the functional domain, the business end, and then there's the guide that tells the editor where to go in the genome to do its job. And each of those pieces, Eric, now there's a mix and match that one can do in terms of modularity. And so that's the kind of approach we're taking to develop something very specific to turn off the Lp(a) gene. And the Lp(a) gene itself is actually a little bit of a challenging target because it's got this multiple repetitive elements in the gene called a kringle IV repeat. It's also got homology to a couple of other genes, fibrinogen, for example, and plasminogen. And so there's some kind of genetic peculiarities that really speak to why you should develop a bespoke editor.

So is it entirely -- sorry, ultimately, is it entirely internally bespoke process that you'll be developing? Or do you need to sort of bring in a collaborator ultimately to...

The work being done right now is internal. I mean we are open to bringing in technologies that might enable that editor development. But right now, the work is internal.

Okay.

So you mentioned developing countries. So what's the clinical plan to expand this drug into developing countries and any partnership you're actively looking for?

We've started to think about that. And I think it's a goal for the next year or 2. Our current focus, as you can imagine, is really looking at VERVE-101 and thinking about understanding the efficacy and safety in the Phase I trial. And with that in hand in the coming year, and having a better sense of what kind of drug product we have, I think we can start to think about expanding out our relationships ex-U.S. But it's certainly a goal in the medium term.

It's a far-looking question, but just with respect to really pricing, assuming approval and ultimately reaching market. I mean how do you think of pricing with VERVE-101 or 201 just given the comps that are on market right now, the -- and really what the payers are able to bear, but also at the same time, just sort of being able to attract a favorable value for the -- for what the product will ultimately deliver for patients.

Yes. I mean, our ultimate goal with these medicines, of course, is to help millions of patients worldwide. And so access is going to be a very important component. I think when people think about gene editing or gene therapies, they automatically have in their head, rare disease pricing, millions of dollars for the onetime therapy. That's certainly not going to be us because we're looking to treat millions of patients. And so if it's not millions of dollars of dose, then what is it? And there are a couple of things that have developed in the last few years that are kind of going in our favor in terms of our drug products. So in 2018, when we started the company, we had already decided then that the drug format was going to be mRNA packaged in the lipid nanoparticle. And then COVID comes along in 2020. It turns out the COVID vaccines look very much like our drug, mRNA packaged in the lipid nanoparticle. And we now know that, that kind of drug product can be made very cost effectively at scale. So that, along with the fact that our addressable markets for any of the indications are very large, gives us a fair amount of pricing flexibility over -- when we get to that point. And I think that will be a key consideration or key considerations as we think about how to make sure this medicine is accessible.

We'll hold for maybe one more question from the floor. If not, I think we'll leave it there. Okay. Great. Well, thanks, Sekar, for your time this afternoon.

Thank you.