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

Good morning, everyone. I'm Anvita Gupta from Cowen's biotech research team. It is my pleasure to introduce Verve Therapeutics for a formal presentation. Verve is making great strides at developing gene editing medicines to treat cardiovascular diseases with the lead program targeting heterozygous familial hypercholesterolemia. Here with us today is Verve's Co-founder and CEO, Sek Kathiresan. We have a little question and answer around at the end, if we have some time. [Operator Instructions] With that, Sek, the floor is all yours.

Thank you very much, Anvita. Really a pleasure to be here. I appreciate the invitation from the Cowen team. So I'm going to share with you the story of Verve Therapeutics. We're looking to transform the treatment of cardiovascular disease from chronic management to single-course gene editing medicines. How are we going to do that? Here are 6 items that really highlight our differentiated strategy and progress. One is we have a first-in-class potent and durable in vivo liver CRISPR base editing medicine. We have a suite of actually complementary single-course gene editing programs, which I'll tell you about. We've made rapid progress on each of these programs using extensive modeling in nonhuman primates. We've coupled that with comprehensive off-target analyses to evaluate for safety. We also have developed a novel lipid nanoparticle or LNP liver delivery platform that I'll tell you about. And lastly, our products are designed for efficient and scalable manufacturing to ultimately reach broad patient populations, not a rare disease, but really the most common cause of death in the world. Now the specific form of cardiovascular disease we're focused on is atherosclerotic cardiovascular disease, or ASCVD. This is blood LDL cholesterol, clogging the heart arteries over time and leading to a heart attack. This is the #1 cause of death worldwide, hundreds of millions of patients worldwide and about 31 million worldwide with a genetic form of the disease called familial hypercholesterolemia or FH. There are 2 forms of FH that you'll hear about, heterozygous FH or HeFH, which is a prevalence of about 1 in 250. And then there's homozygous FH, HoFH, which is a prevalence of about 1 in 250,000. Our products will address both of these diseases. Now the current standard of care for ASCVD, the chronic care model results in poor control of blood LDL exposure. And that's what's highlighted on this graph on. The x-axis is age on the y-axis is the LDL cholesterol for a hypothetical patient with HeFH. The patient is born with an LDL cholesterol that's very high, about 200 and untreated for 4 decades until a heart attack at age 44. Now the primary treatment once you have a heart attack is to lower the LDL as low as possible for as long as possible. Now in the standard of care model that's accomplished with pills, daily pills or intermittent injections, and that's what's shown here. With standard of care, the LDL comes down, but doesn't stay down. There's oscillation in the LDL cholesterol over the life course that, as you can see, the up and down over the years. And that lack of control leads to recurrent heart events like another stent or bypass surgery or even a fatal heart attack. Now why is there this oscillation? And you can see some of the reasons in the bottom: adherence, access, all issues with current standard of care. So what Verve is looking to do is replace this model with what's shown here, a onetime treatment, dramatic lowering of LDL cholesterol, durable lowering of LDL cholesterol to address that unmet need of cumulative LDL control. We want to get the LDL as low as possible for as long as possible, and we propose to do that with single-course gene editing medicines. Now we're advancing a pipeline of such medicines to safely and durably switch off disease-causing genes in the liver. Our first 2 programs are shown here: VERVE-101, targeting the gene PCSK9; and the second program targeting the gene ANGPTL3. I'm going to walk you through the progress for each of the 2 programs. For VERVE-101, we're on track to treat the first FH patient in the second half of this year, second half of 2022. Now as I mentioned earlier, familial hypercholesterolemia or FH is a genetic form of ASCVD. It's a morbid disease characterized by high cumulative exposure to LDL-cholesterol and premature heart attack and stroke, often in the 30s, 40s and 50s. As I said earlier, 31 million people worldwide and FH is associated with a dramatically elevated risk of ASCVD over a lifespan. And the chronic care models for these patients is particularly burdensome because it requires early intervention and requires many medicines taken daily or intermittent injections. What we want to do is replace that chronic care model with single-course gene editing medicines that are schematized here, a onetime infusion, intravenous infusion into the bloodstream. That medicine makes its way to the liver into the liver cells. And then there is a single spelling change made in the nucleus, in the DNA of the liver cell. And that intended effect of that single spelling change, an A to G spelling change is to turn off a disease-causing gene. In the case of our first product, the Gene PCSK9. The consequence of that is the blood PCSK9 protein level goes down and ultimately leads to dramatic lowering of LDL-cholesterol. Now it's a dramatic lowering and importantly, a durable lowering. We expect this lowering to be there for the lifetime of the animal or patient. Now here's the drug product, VERVE-101. It's an adenine base editor, mRNA and a guide RNA targeting the base editor to the PCSK9 gene, both of those nucleic acids are packaged in a lipid nanoparticle. That's what's shown on the left and then electron micrograph on the right. The base editing that happens is a single base pair change in the PCSK9 gene that switches off the gene permanently. Now for VERVE-1, we've conducted an extensive IND-enabling program and it's on track to be completed in the first half of this year. And several of the studies as part of that program are shown here, including toxicology study in the mouse model of disease, durability studies in nonhuman primates and durability studies in mouse models as well as comprehensive off-target analyses in liver cells as well as other cell types. And I'll walk you through some of the results of these studies in the next few slides. Here's one. This is a durability study in nonhuman primates with VERVE-101 given to several groups of monkeys, one dose, 0.75 mg per kg dose, a 1.5 mg per kg dose and then vehicle control. As I mentioned, this is given as an intravenous infusion at one time point. There are several endpoints that have been measured in these monkeys at 2 weeks and then serially out now to 6 months plus. The endpoints include liver DNA editing assessed by sequencing. The blood protein level, blood PCSK9 level and the blood LDL-cholesterol level as well as safety endpoints. Here are some of the results. Shown on the x-axis is age bar is a monkey. On the y-axis is the percentage decrease in the plasma protein made by the PCSK9 gene, the PCSK9 protein. What you can see is the vehicle control, there's really no change, net in the monkeys, in the 10 monkeys. But in the VERVE-101-treated monkeys at 1.5 mg per kg, there's about an 86% reduction in plasma PCSK9 protein. That's because there's about a 70% editing rate in the liver at the intended target site. You can see also remarkable consistency monkey to monkey in the protein reduction. This was at 2 weeks. What about over time? This is the blood PCSK9 level over time on the x-axis, days post infusion. On the y-axis is the percentage of PCSK9 reduction in vehicle in gray, and then the 0.75 mg per kg in blue and 1.5 mg per kg in purple. What you can see at the 1.5 mg per kg dose, there's about an 80% to 90% reduction in plasma PCSK9 level. This is a reduction in the blood LDL level. There's about a 60% to 70% reduction in the blood LDL level at 2 weeks and then it stays durably low over 6 months plus. Now these are all data with VERVE-101. We also have much longer-term data with a precursor formulation that is close to VERVE-101. And this is data now almost 15 months after treatment with that precursor formulation. Again, blood PCSK9 on the left and blood LDL on the right, which you can see is that after a onetime treatment, you're getting dramatic and durable reductions of both endpoints. As I said earlier, we expect this to be durable for the lifetime of the animal and lifetime ultimately of the individual patient treated with VERVE-101. Here's some safety data on the X-axis days post infusion, on the Y-axis is on liver function test marker, ALT. And what you can see is there's a transient rise with -- in ALT that comes back down to normal within a couple of weeks and stays normal for the full duration of the follow-up. This transient rise is expected with lipid nanoparticle infusions. But importantly, as I said, there's no issues over the long run. These are off-target data -- off-target analysis data. On the x-axis are a set of chromosomal sites, about 3,000 of them that are candidate off-target sites that we've looked at. On the Y-axis is the net adenine editing at each site. And this is data from liver cells, primary human liver cells treated with drug, treated with VERVE-101. What we're seeing is that there's excellent editing at the on-target site in the PCSK9 gene. That's the purple dot. But all of the potential off-target sites on the X-axis, they're all centered around 0, meaning there's no net adenine editing. So this is an exquisite level of specificity that we're getting with our drug product. It's a function of both the editor and the specific guide RNA that we've chosen to make this single base per edit. Here's the schematic for the clinical Phase I study. This is on track again for clinical initiation in the second half of this year. We plan to treat about 40 patients with heterozygous FH that are molecular diagnosis -- with a molecular diagnosis, an LDL that's unacceptably high on standard of care. And 3 dose groups, low, medium and high. In the part A, select the appropriate dose and then expand in Part B. The major endpoints are safety endpoints, the blood PCSK9 level as well as the blood LDL level. And we expect the safety and the efficacy endpoint to change within a couple of weeks after treatment. Now the development strategy beyond the Phase I is really stepwise. We intend to start with the FH patient population in Phase I, Phase II, Phase III, but then expand to even broader patient populations with or at risk for ASCVD. So going from HeFH, which is about 31 million people globally, ultimately, we will expand to patients with established ASCVD. This is now about 8% of the U.S. and the world. And then ultimately, this could be a preventive medicine for patients at risk for ASCVD before they have the heart attack. So there is a plan to successfully expand the addressable market from HeFH to garden variety ASCVD to ultimately prevention. Now the second program, the ANGPTL3 program has also made considerable progress and right now is in IND-enabling study stage. The second program is intended to turn off the ANGPTL3 gene with base editing and ultimately lower LDL and treat ASCVD as well. Now ANGPTL3 is a target, just to give you a bit of background. This is a compelling target to lower blood LDL-cholesterol. And the evidence comes from both human genetics on the left and human pharmacology on the right. There are people walking around who have this gene completely turned off naturally due to human mutations. And what they have are very low LDL-cholesterol levels and they're resistant to heart attack. These observations gave rise to the idea that one could develop a medicine to mimic the mutations and help patients. And one medicine that's been developed is evinacumab, a monoclonal antibody targeting ANGPTL3. And that's been shown in both HeFH patients as well as HoFH patients to potently lower LDL-cholesterol. And it's approved for use in the U.S. for patients with HoFH. Now what we're looking to do is develop a one-and-done medicine to turn off ANGPTL3 permanently in the liver and particularly start with HoFH patients. Now there is a delivery challenge here in this patient populations because HoFH patients completely lack the LDL receptor. That's what's shown all the way on the right. You see normal liver patients and HeFH patients on the left and the middle. Now in this setting, lipid nanoparticles, standard lipid nanoparticles don't work because standard lipid nanoparticles get taken up by the liver through the LDL receptor. So in HoFH patients that completely like the LDL receptor, the standard lipid nanoparticles don't deliver. So we had to overcome this problem if we want to treat HoFH patients with our ANGPTL3 base editing medicine. And what we've done is created a new LNP, a targeted LNP, GalNAc LNP that can get into the liver through a receptor other than LDL-R, a receptor called the asialoglycoprotein receptor, ASGPR. So our GalNAc LNP shown on the left is basically a standard LNP with a GalNAc targeting ligand added to it and carrying our base editor mRNA and a guide RNA. And this GalNAc LNP can now make its way into liver cells in HoFH patients. That's the hypothesis. So we had to test this, and we tested it initially in mice and then showed it can work in mice-lacking LDL receptor and then went on to test in monkeys. We first tested -- we first created a homozygous FH monkey model, where the LDL receptor was knocked out in the liver and came in with the standard LNP carrying our ANGPTL3 base editor. And what we saw, as expected, is that the standard LNP didn't work. So there's no editing on the left, and there's no change in plasma ANGPTL3 level on the right. In standard -- in HoFH monkey model treated with the standard LNP carrying our ANGPTL3 base editor. But then when we delivered the base editor, the ANGPTL3 base editor using our GalNAc LNP, you can see here excellent editing, on average, about 60% whole liver editing on the left and then a dramatic lowering of the plasma ANGPTL3 level on the right because the ANGPTL3 gene has been switched off. Now we repeated this experiment and what you can see is that in a monkey model of homozygous FH treated with the ANGPTL3 base editor carried in our GalNAc LNP, we're getting now 94% to 97% reduction in plasma ANGPTL3. So we're basically able to completely shut down the gene in the liver. Now let me close in the last few slides on kind of thinking through this question of how will we deliver on our promise of single-course gene editing medicines to train cardiovascular disease. We have developed core capabilities in several areas to really enable product development. I mentioned our internally developed novel lipid nanoparticles. We have capabilities in guide RNA design and purification, mRNA design, purification and GMP production and finally, comprehensive off-target analysis. We put all these capabilities together to enable rapid product development with iteration in -- largely in monkey models. The team that's enabled all this progress is shown here, a world-class team to nimbly solve problems. Let me close with this slide. This is our milestone -- a set of milestones for this year, really looking to be a very transformative year for the company. For VERVE-101, the key transition will be a preclinical to clinical. We'll be dosing our first patients in the second half of the year. For the ANGPTL3 program, we anticipate lead candidate selection in the second half of the year, followed by initiation of IND-enabling studies. And in addition, we have a couple of other major goals for the year. One is to expand the pipeline beyond the first 2 products for additional in vivo liver gene editing programs. We also expect to establish the GalNAc LNP delivery system as a leading platform for in vivo liver delivery. And lastly, we plan to strengthen our team to enable all of these milestones. Thank you very much. Let me close here.

Great. Thank you, Sekar. So it looks like a very -- you set up to a very transformative year and a very [ cashless ] switch probably next year as well, right? So looking forward to that. We have a few questions, and we do have some time. So I guess before I can ask some high-level questions, there's a pointed question from a listener regarding your 101 program, the NHP data where -- regarding the vehicle control, where there's more variability in the blood PCSK9 level seen in the vehicle control after dosing, but the blood LDL-C level is actually pretty stable. So is there an explanation you can give towards that why that discrepancy might be there?

The variability is just due to the small number of monkeys in the vehicle control. I think the vehicle control was maybe 6 monkeys whereas the treated group is more like 30 monkeys. So it's really just a function of the number of animals.

Got it. Okay. And I guess I can move on to some of my high-level questions here. So what's the range of patients that you ultimately see as being an addressable patient population maybe looking at a 10-year view from now with your candidates?

Yes. I think that's one of the key differentiating factors of Verve. We're really -- most companies that are focused on gene editing or gene therapy or looking to treat rare disease or oncology. As I said earlier, we're looking to tackle the world's leading cause of death. And so the number of addressable patients here for FH is about 1 million people in U.S., 1.3 million in Europe and overall 31 million globally. So it's a very large genetic disease. And we're looking to be a curative approach for their high-LDL-cholesterol. For ASCVD, as I mentioned, it's about 22 -- it's about 8% of the U.S. So it's about 22 million patients in the U.S., probably 25 million to 30 million in Europe and a couple of hundred million globally. So again, really large patient population. And then if you go to the third group of prevention, that's even larger.

Right. And I think that's where -- when we speak to our base editing experts, that's what they say we are going from treatment -- we could go from treatment to preventative medicine eventually. First, you need to prove in treatment as well.

And I think it's important to emphasize that the treatment -- addressable market for the treatment groups, the treatment population is incredibly large and then before you even get to the prevention.

Exactly. And then I wanted to touch about -- touch on your -- the sequential dosing experiment. So you're exploring PCSK9 and ANGPTL3 for sequential dosing. So broadly speaking, in our coverage universe, we see Alnylam also trying to pursue the GEMINI platform by conjugating 2 siRNAs, targeting 2 different targets in ANGPTL3 and angiotensinogen. So do you think that's where the field is moving in the few years with dual targeting? Is that a reasonable thing to think about the approach as with editing or RNAi?

Yes. Ultimately, the way to think about this, at least for [ atheros ] cardiovascular disease is that there are 3 independent risk pathways in the lipoprotein axis. So one is LDL and PCSK9 kind of gets at that. The other is this LDL plus triglycerides, triglyceride-rich lipoproteins and ANGPTL3 gets to that. There's a third axis called lipoprotein (a) and the LPA gene, one of our other targets we're looking to pursue get to that. And so if each of these 3 pathways were permanently disabled, it's almost impossible to get a heart attack.

Right.

So I think the ultimate vision for Verve is develop medicines that would address each of these pathways. And then how they're given, whether they're given individually in succession or all in a single combo. That will depend on the patient and I think the regulatory process over the next few years.

Got it. Okay. That's very helpful. We have one final question come in, and this is something that we think about all the time, with gene therapies, with nonviral methods, et cetera. So have you done any work on the biodistribution of the LNPs and ex liver edits that your candidates might make? And what might be the main drivers of risk that 101 might miss on the end point?

Yes. Great question. Yes, we've done extensive work on biodistribution of the lipid nanoparticles. I think it's important to emphasize that we selected the lipid nanoparticles in nonviral delivery 3, 4 years ago. And it has incredible set of advantages over viral delivery in terms of safety, redosability, manufacturing costs. And again, we selected this 4 years ago. And COVID, with the mRNA vaccines look very much like our drug and really has shown the world that this kind of format of mRNA package and lipid nanoparticle can be manufactured at scale very cost effectively. So that's a very important development. Now the difference, of course, is that we're infusing systemically. And so we have to check where else does it go beyond the liver. And for our LNP, there are 2 other places it goes, spleen and adrenal gland. And so we have been evaluating on-target and off-target editing in those tissues as well. Now in terms of on-target editing, there are patients walking around who have the PCSK9 gene turned off in every tissue in their body, so-called human knockouts. And they're healthy. They have very low lipid levels, they're resistant to heart attack. So we know that even if there's on-target editing in organs other than the liver, it's not really an issue. But for off-target editing, we're in the process of evaluating in other tissues beyond the liver and stay tuned.

So could we expect some data updates at the upcoming gene therapy meetings?

Yes. So we are -- we will be presenting at the American College Cardiology coming up. We'll be presenting at TIDES and we'll be presenting at the American Society of Cell & Gene Therapy.

Awesome. That's great to hear. All right. We have -- I don't see any further questions. So we're almost at time here for this session actually. So on behalf of Cowen, I would like to thank you, Sek, for the wonderful presentation and to our audiences for joining in. The next session will begin very shortly. Thank you.

Thank you very much.