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

The afternoon session of Day 2 of the Bank of America Healthcare Conference. I'm Greg Harrison, one of the biotech analysts here at BofA. And today, it's my pleasure to introduce Sek Kathiresan, CEO of Verve Therapeutics. Take it away, Sek.

Thank you very much, Greg. Really a pleasure to be here. Happy to share the Verve story with you all. Okay, the problem we're trying to solve is atherosclerotic cardiovascular disease. This is really a problem of LDL cholesterol clogging the heart arteries. It's a leading cause of death worldwide, hundreds of millions of patients worldwide. And we're initially focused on a genetic subset of the disease called familial hypercholesterolemia, specifically heterozygous FH and then homozygous FH. And there are about 31 million people in the world with this genetic subset of atherosclerotic cardiovascular disease. Now the solution to atherosclerotic cardiovascular disease has been revealed by human genetics and human pharmacology. And this article written by Dr. Eugene Braunwald, one of the real pioneers of American Cardiology is entitled how to live to 100 before developing clinical coronary heart disease. And the answer that he proposed was very simple, to get one's LDL cholesterol as low as possible as long as possible. Now in the current chronic care model for ASCVD, there's actually very poor control of LDL cholesterol. This is illustrated in this hypothetical patient with FH on the X-axis is age, on the Y-axis is LDL cholesterol. And what you can see is this person was born with an LDL of about 200, and then at age 44 has a heart attack, gets put on medicines to lower LDL. The LDL does come down but doesn't stay down over time. There's tremendous oscillation in the LDL cholesterol over the life course because of issues like adherence, access, the requirement for health care infrastructure. So this is what's happening every day in clinical practice. If you take 100 patients with atherosclerotic cardiovascular disease today, they all need to be on LDL lowering medications. In fact, only about half are actually on any medication to lower LDL cholesterol. What we'd like to do is to replace this picture with this picture. A onetime therapy, dramatic lowering of LDL cholesterol and durable lowering of LDL cholesterol to really achieve this goal of getting a LDL as low as possible for as long as possible. And we want to accomplish this with single course gene editing treatment, and this really has the potential to address this unmet need. Now how are we going to do that? We're advancing a pipeline of single course in vivo gene editing programs to safely and durably lower LDL cholesterol to treat ASCVD. Our first 2 programs are shown here. The first targets the gene PCSK9. The second targets the gene ANGPTL3. And you can see the initial clinical indications are both genetic subsets of the disease for each of the 2 programs, heterozygous FH and homozygous FH, respectively, and then expanding out to atherosclerotic cardiovascular disease after that, and I'll show you that in a couple of minutes. Now one of the exciting developments for the company, as of yesterday, we announced that the -- there's been a clearance, a CTA clearance for the VERVE-101 program, giving us permission to treat our first patients and this is from the New Zealand health authorities. And later this year, we expect clearances from the U.K. and U.S. as well. Now VERVE-101 is on track to treat the first heterozygous FH patient in mid-'22. Here's the preclinical data that's really gotten us to this point. First is just telling you a little bit about the drug. This is a gene editing medicine. Specifically, it's using an adenine base editing technology, in-licensed from Beam Therapeutics and a guide RNA that targets the PCSK9 gene, both of these are packaged in a lipid nanoparticle. That's what's shown on the left, schematized on the right is the electro micrograph. The edit that's made by this editor is an A to G spelling change in one spot in the PCSK9 gene sequence and the intended consequence is to turn off the gene and shut down protein production from the liver. This is the schematic of the pharmacology. The medicine is given as a onetime infusion, as shown all the way on the left. After infusion to the bloodstream, the drug particles make their way to liver, they're internalized by liver cells. The internal contents, the mRNA and the guide RNA are released into the cytoplasm, the mRNA is translated into adenine base editor protein that protein binds to the guide RNA, and that complex ultimately makes its way to the nucleus of the cell and scans the entire genome, chromosome by chromosome until it lands on the spot dictated by the guide RNA. In our case, we intended to go to the conical supply side at the end of exon 1 in the PCSK9 gene. There's an A to G spelling change that's made at that spot, and that disrupts the supply side and turns off the gene that way. The consequence is reduction of blood PCSK9 protein level and ultimately, LDL level. So this is all the theory. How do we -- this is work. And these are the preclinical data. This is in nonhuman primates for VERVE-101. Three groups of monkeys, vehicle control, VERVE-101 at 0.75 mg per kg in blue and VERVE-101 in purple is at 1.5 mg per kg. You can see a very large study, 4 monkeys and 22 monkeys in the 2 treated groups. And on the X-axis is time, on the Y-axis is the blood PCSK9 protein level. What you can see is that in the 1.5 mg per kg group, the PCSK9 protein level comes down by about 90% at 2 weeks and then a year later, the blood protein level is still down 90%, reflective of essentially the entire liver in all the liver cells, this gene being edited and turned off. This -- the consequence of this level of PCSK9 protein reduction is a dramatic lowering of LDL cholesterol in the blood. This is again the same monkeys on the X-axis is time and the Y-axis now is LDL cholesterol. And what you can see is in the 1.5 mg per kg group, the LDL cholesterol was down by 68% at 2 weeks and then Rock study, 68% down at 1 year after treatment. So this is truly going to be a one and done, durable lowering of LDL after a onetime therapy. This is data for the clinical formulation of VERVE-101. We have even longer term data, longer durability data with a precursor formulation. And here, the X-axis is out to 600 days. And you can see with this precursor formulation, again, durability for PCSK9 level on the right and LDL level on the right. Sorry, PCSK9 level on the left, LDL cholesterol level on the right. Now that's all on target effect. What about off target? Are we making any of these spelling changes, anywhere else in the genome. There's been an extensive amount of work done by Verve to evaluate this. This is just one figure to get at this concept. On the X-axis are about 3,000 different spots in the genome sequence, both the on-target site and all about 3,000 potential off-target sites. On the Y-axis is editing at any of these spots. And what you can see is that in primary human liver cells treated with drug, there is no observed off-target editing in any of the 3,000 candidate sites in primary human liver cells. So this is an exquisite level of specificity. That is a function of both the guide and the adenine base editor protein that pair that we're selecting. Now with these preclinical data and a bunch more actually, put together, we were able to obtain clearance for a first clinical trial application for VERVE-101 from the New Zealand health authorities, as I mentioned earlier. This is really a first for in-vivo liver base editing. And this gets us in shape to dose our first patients in the middle of '22. And then we -- our guidance is for the second half of '22 for clearances, CTA clearance in the U.K. as well as an IND in the United States. Clinical data for this program is expected in 2023. This is the clinical trial design for the Phase I. We're going to be treating patients with heterozygous FH who've already suffered a heart attack who have unacceptably high LDL cholesterol, LDL over 100 on oral standard of care. About 40 patients, 4 dose groups in a single ascending dose design, the goal of that Part A is to identify an efficacious dose, then that dose is expanded into a larger patient population in Part B and then followed for endpoints of safety, the LDL cholesterol as well as PCSK9. We expect the LDL cholesterol and the PCSK9 level to drop within a couple of weeks. So the readouts here should be relatively quick. The study is intended as a 1-year follow-up study. Now that's the Phase I, and that's really in heterozygous FH subset. Our stepwise development strategy, starting with FH and expanding to broader population with ASCVD is outlined in this slide. You have the HeFH population, where I mentioned the Phase Ib, proof of concept. The next group would be all HeFH, which would be Phase II as well as a pivotal Phase III with an LDL endpoint at 24 weeks. Please note that for every prior LDL-lowering medication approval in the heterozygous FH patient population has been based on LDL cholesterol alone. And heterozygous FH, there's about 1 million patients in the United States, 1 million in Europe and about 31 million globally. So this is a very large genetic disease where our treatment is set up to be a genetic cure for the high LDL. We expect to expand beyond this group to atherosclerotic cardiovascular disease. And this is about 24 million patients in the United States, hundreds of millions of patients globally and a pivotal Phase III here, again, with an LDL as the approval endpoint. Finally, there are additional post-approval studies to enhance adoption in the ASCVD group that we might entertain. That's the first program. The second program targets the gene ANGPTL3. Again, this is a gene where targeting this protein has lower LDL cholesterol and is a mechanism that is independent of the PCSK9 mechanism, so it will be additive in terms of LDL lowering effect to PCSK9 in activation. This program, we expect to advance to IND-enabling studies in 2022 after naming a development candidate in the second half of this year. Here is the schematic of how this drug works, and you can see it's actually quite similar in theory in terms of using base editing to turn off this gene. Here are the preclinical data initially in monkeys here, where you can see here that the editing of this gene has essentially turned off the gene completely switched off the gene completely. We're getting 96% reduction in the plasma ANGPTL3 protein at about 2 weeks. And then here, the follow-up is out to, again, 600 days. And you can see that there's tremendous durability. In addition, in terms of safety profile, there are no long-term impacts on liver function tests, in terms of ALT or total bilirubin. Now the lipid nanoparticle that's being used here for this program is actually proprietary and developed within Verve. And this is a GalNAc lipid nanoparticle technology, and we have developed some evidence to suggest that this might end up being a best-in-class for liver delivery of genetic medicines. This lipid nanoparticle differs from those -- the standard lipid nanoparticle in the -- by the addition of the GalNAc targeting ligand to the surface. And with the addition of the GalNAc targeting ligand, this LNP is able to get into liver cells using the ASGPR receptor, the asialoglycoprotein receptor. These are data in a monkey model of homozygous familial hypercholesterolemia and we're able to show here that with this GalNAc LNP, we're able to get in the editor and edit and turn off the ANGPTL3 gene and having ANGPTL3 reductions of 94% to 97%. And this will translate to about a 50% reduction in LDL cholesterol in patients. Now as I mentioned, the GalNAc LNP was developed for this indication of homozygous FH. But it's emerging as potentially a best-in-class for liver delivery in wild-type patients, individuals and in data from data shown here in wild-type nonhuman primates. So this is data in wild-type monkeys, where we tested the GalNAc LNP compared to a standard LNP for the ability to edit. On the X-axis, our 3 dose groups, in purple is a standard LNP, in blue is a GalNAc LNP delivery, and each dot represents a monkey. On the Y-axis is adenine editing at the ANGPTL3 target site. And what you can see is for each dose, the blue bars, so the GalNAc LNP performs better, it's more potent. What this translates into is pretty dramatic reductions in the plasma ANGPTL3 protein. And again, here, look at the blue bar all the way on the right. Here, we're seeing about a 98% reduction in plasma ANGPTL3 with the GalNAc LNP delivery mechanism, and it's more potent than the standard LNP. In addition, it's more consistent. Each of the black bars is -- each of the black dots are -- they're tighter closer together compared to those for the blue bars. Now let me close by telling a little bit about the capabilities that Verve has developed to become a leader in the development of in-vivo liver gene editing medicines. The core capabilities we have developed over the last 4 years since the company formation in 2018 are shown here. One is development of lipid nanoparticles. Second is focus on guide RNA, design and purification. Next is mRNA design, purification and production. And lastly is comprehensive evaluation for off-target profile. We put all these capabilities together in the context of rapid product development in -- focused on nonhuman primate studies. Now this leads us to what can you expect from us over the next 9 to 12 months. So the key milestones for the company as we transition from a preclinical to a clinical stage company are as follows: number one, dosing of the first patient in the middle of this year. Second is we expect a U.K. CTA clearance. Third is we expect the U.S. IND clearance. Fourth is naming a lead candidate for the second program, the ANGPTL3 program and kicking off IND-enabling studies. And lastly, is the clinical data for VERVE-101, the first program in the Phase I study, we expect in 2023. Thank you.