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

Good morning, and welcome to the Verve Therapeutics conference call. [Operator Instructions] Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Jen Robinson, Senior Vice President of Investor Relations and Corporate Communications. Please go ahead.

Thank you, operator. Good morning, everyone, and welcome to Verve's conference call to review the initial data from the ongoing Heart-2 Phase Ib clinical trial of VERVE-102. Slides for this call and a replay of the event will be available on the Investors section of our website at www.vervetx.com. Before we begin, allow me to introduce our speakers and walk through the agenda for today's call, Dr. Sek Kathiresan, our Co-Founder and Chief Executive Officer; will share some opening remarks, including an overview of our PCSK9 program. Next, Dr. Scott Vafai, our Senior Vice President of Clinical Development, will present initial results from the Heart-2 clinical trial. Sek will then cover next steps for VERVE-102 and provide closing remarks before we open it up for the Q&A portion of the call, where we will be joined by Ms. Allison Dorval, our Chief Financial Officer. At this time, I'd like to take a minute to remind everyone that any statements we make or information presented on this call that are not historical facts are forward-looking statements that are based on our current beliefs, plans and expectations, and are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties and other factors, including those set forth in the Risk Factors section in the most recent annual report on Form 10-K and any other filings that we may make with the SEC. You are cautioned not to place any undue reliance on these forward-looking statements and Verve disclaims any obligation to update such statements unless required by law. With that, let me turn the call over to Sek.

Thank you, Jen, and good morning, everyone. Verve's mission is to transform the care of cardiovascular disease from chronic care to a one-dose future. I'll start with a brief overview of our indications, the addressable market, and the underlying biology of cholesterol-driven atherosclerosis. We're focused on two indications: atherosclerotic cardiovascular disease, abbreviated ASCVD, and heterozygous familial hypercholesterolemia, abbreviated HeFH. ASCVD and HeFH are highly prevalent diseases with a profound need for improved treatments. ASCVD is a buildup of cholesterol-driven plaques that ultimately cause serious cardiovascular events. HeFH is an inherited disease characterized by extremely high levels of LDL leading to early onset ASCVD. ASCVD is the leading cause of death in the world and approximately 75% of patients are not at LDL goal. HeFH affects more than 3 million people in the U.S. and European Union. Remarkably, 97% of HeFH patients are not at LDL goal. We urgently need a new treatment approach to achieve deep and durable LDL reductions in both patient populations. In both indications, over time, atherosclerotic plaque progresses in the wall of the heart artery, leading to acute ASCVD clinical events such as sudden cardiac death or nonfatal heart attack. The foundation for both treatment and prevention of ASCVD is the same, keep blood cholesterol as low as possible for as long as possible and start treatment as early as possible. We already have several options available to lower blood cholesterol. So what's the unmet need? Today's chronic care approach leads to transient LDL reduction and inadequate efficacy. For example, lowering LDL by 40-milligram deciliter over a 5-year period is associated with just a 21% reduction in cardiovascular risk. And even this level of efficacy is compromised by frequent discontinuation. Shown here are the discontinuation rates for two available injectables targeting PCSK9. For an siRNA injection given every 6 months, approximately one in five patients discontinued therapy within 1 year. For a monoclonal antibody injection given every 2 weeks, approximately one in two have discontinued within 1 year. Now these are discontinuation rates at just 1 year for therapies that require decades of use. What's the clinical impact of this discontinuation? Pretty dramatic. These products are labeled with a 50% to 60% LDL lowering. However, data presented at the recent American College of Cardiology Conference show that the estimated real-world LDL reduction at 1 year is only 25% to 35%. So what's the solution to the unmet need for improved efficacy? What we need is a new treatment approach that can provide enduring efficacy. Shown on this slide is the impact of that same 40-milligram deciliter of LDL lowering based on a naturally occurring human mutation that inactivates PCSK9. 40 milligram deciliter of LDL lowering over a lifetime can safely reduce ASCVD risk by up to 89%. This is because the benefit of LDL lowering accrues over time and is maximized when started early and durably maintained. We believe we can change the way cardiovascular disease is treated by developing a medicine that mimics this profound human genetic observation. Verve's vision is a one-dose future to address chronic disease, a single IV infusion that leads to lifelong blood cholesterol reduction and solves the unmet need of enduring efficacy. Now cholesterol in the blood is carried in any of three carriers: LDL, triglyceride which lipoproteins abbreviated TRL and lipoprotein(a). Our pipeline is built to address these three cholesterol drivers of atherosclerosis. Prior to the founding of Verve, work from my academic research labs as well as others have validated PCSK9, ANGPTL3 and LPA as compelling targets for the treatment of ASCVD. Today, we'll focus on VERVE's PCSK9 program. As a reminder, we've developed two PCSK9 program product candidates, VERVE-101 and VERVE-102, both have the same base editor and guide RNA targeting PCSK9. VERVE-101 and VERVE-102 differ in their delivery approach. We developed a new GalNAc-LNP delivery platform and this technology is what is being used in VERVE-102. GalNAc is a liver targeting ligand that allows for LDLR independent uptake into hepatocytes as illustrated here. After IV infusion of the GalNAc-LNP, VERVE-102 is able to enter hepatocytes through one of two routes, either the LDL receptor or the GalNAc receptor, which is called ASGPR. With this established, I want to outline the questions we'll address during the next part of our presentation. First, safety. Does the novel GalNAc-LNP used in VERVE-102 allow for safe delivery of the gene editor to the liver? Second, efficacy. What dose of VERVE-102 might drive a potent LDL reduction? Third, durability. Can potent LDL reduction be maintained over time? Let's begin with the third question. We'll start by providing a durability update for VERVE-101 from the Heart-1 clinical trial. I'm excited to show for the first time 2-year clinical durability data for any base editing product. Shown on the x-axis is time, shown on the y-axis is LDL percent change from baseline. At 2 dose levels, we can clearly see there has been great durability of effect. For the patients in the 0.6 mg per kg dose level, the purple line, 2 years after a single intravenous dose time average LDL reduction has been 58%, truly remarkable. This purple line highlights the young man who entered our study before the age of 30, having already suffered a heart attack, which was treated with a coronary stent. And his LDL has been at goal for a full 2 years after the single infusion. This patient's experience shows the potential to realize our vision of enduring efficacy. However, LNP-driven transient laboratory abnormalities occur right after dosing of VERVE-101. In April of 2024, this motivated us to prioritize VERVE-102 as our lead product candidate for the PCSK9 program. Exactly 1 year later, we're now ready to address the 2 remaining questions for the PCSK9 program, safety and efficacy of VERVE-102. I'll now hand it over to Dr. Scott Vafai, our Senior Vice President of Clinical Development, to walk you through the emerging answers for these two questions.

Thank you, Sek. In the next set of slides, I will review the initial results from the Heart-2 first-in-human clinical trial of VERVE-102. The ongoing Heart-2 open-label Phase Ib clinical trial of VERVE-102 is being conducted in two patient populations who require deep and durable reductions of LDL levels in the blood. Adults living with HeFH and/or premature coronary artery disease or CAD. VERVE-102 is given as a single dose administered as a 2- to 4-hour infusion through a peripheral IV. The Heart-2 clinical trial is expected to include 4 dose group, each comprised of 3 to 9 participants with HeFH and/or premature CAD. Our goal is to evaluate the safety and tolerability of VERVE-102, evaluate pharmacokinetics of VERVE-102 and measure changes in blood PCSK9 and LDL levels following a single infusion of VERVE-102. Today, we are excited to present data from 14 participants dosed across three weight-based dose groups with at least 28 days of follow-up for each participant as of the data cutoff date of March 13, 2025. This includes 4 participants dosed at 0.3 milligrams per kilogram, 6 participants dosed at 0.45 milligrams per kilogram and 4 participants dosed at 0.6 milligrams per kilogram. Shown here are the baseline characteristics for the 14 participants that have been dosed. Mean baseline LDL cholesterol was 140 milligrams per deciliter. The mean age of participants was 52 years. We enrolled a mix of male and female participants. 8 of the 14 participants have HeFH only, 3 participants at both HeFH and premature CAD, and 3 participants have premature CAD only. The majority of participants were on a high-intensity statin. We will now review safety. VERVE-102 is well tolerated across all dose levels with no treatment-related SAEs or DLTs, no clinically significant laboratory abnormality and no cardiovascular events. Across all 14 participants, there was only one infusion-related reaction, which is a single grade 2 infusion-related reaction in a participant dosed at 0.6 milligrams per kilogram. The symptoms were transient and resolved with acetaminophen. So overall, a reassuringly clean clinical safety profile. This slide provides a more detailed view of the adverse events. The majority of adverse events were mild in severity and unrelated to treatment. And importantly, there were no serious adverse events related to VERVE-102 treatment. Moving to lab safety. This slide shows the mean alanine aminotransferase or ALT values by cohort during the first 28 days following VERVE-102 infusion. Each panel represents a dose level with the lowest dose of 0.3 milligrams per kilogram on top and the highest dose of 0.6 milligram per kilogram on the bottom. The y-axis is the ALT level and the x-axis is time and date. There were no clinically significant changes in ALT at any dose level following VERVE-102 infusion. There were no dose responsive trends in ALT. Notably, at the highest dose level of 0.6 milligrams per kilogram, none of the patients had an ALT above the upper limit of normal following the infusion. This slide shows the AST and bilirubin values. The AST is on the left and bilirubin is on the right. Similar to ALT, there were no clinically significant changes in AST or bilirubin at any dose level following VERVE-102 infusion. And here, the platelet values, which are flat, showing no clinically significant changes. Historically, LNP-driven laboratory abnormalities have been characterized by transient changes in liver function test and/or platelets in the post-dosing period. We are delighted to observe that there were no clinically significant changes across our 3 dose cohorts, including the highest dose cohort, and there were no dose responsive trends. Let's turn now to pharmacodynamics. Here are the PD data for blood PCSK9 protein reduction. Each bar represents a weight-based dose group. The y-axis represents the percent change from baseline of the blood PCSK9 level, time average from day 28 onwards. As anticipated for our mechanism of action, we saw dose-dependent reductions in PCSK9 with a mean reduction of 60% observed in the highest weight-based dose group. Here are the LDLs presented in the same way with the y-axis representing the percent change from baseline to the LDL, time average from day 28 onwards. Again, we saw a dose-dependent reduction in LDL. Mean reduction was 21% in the 0.3 milligram per kilogram group and 41% in the 0.45 milligrams per kilogram group. In the 0.6 milligram per kilogram group, we are thrilled to observe mean reduction in LDL of 53%. I'd now like to spend a moment discussing another way to evaluate the data by fixed doses of total RNA in milligrams. Over the past few years, the in vivo gene editing field has moved towards this kind of fixed dose approach to treatment. The schematic on the left shows the 2 RNA drug substance, the adenine base editor and the guide RNA in the center of VERVE-102. Total RNA dose refers to the total weight in milligrams of this RNA cargo. Of note, the amount of RNA administered depends on the weight of the patient. For example, in the 0.6 milligram per kilogram group, a 60-kilogram person would receive 36 milligrams of total RNA but a 100-kilogram person would receive 60 milligrams of total RNA. The next set of slides show the PD data analyzed based on total RNA administered in milligram. Here, we're applying the relationship between percent change from baseline LDL on the y-axis versus the total milligrams of RNA of VERVE-102 administered on the x-axis. We thought it would be most insightful to share the LDL reduction for each patient in this segment. Each purple dot here represents a single patient LDL reduction. Across the 14 patients, a strong near linear relationship emerges between dose of RNA administered and degree of LDL reduction. Across all 14 patients, the LDL reductions range from about 10% to a maximum of 69%. A review of this relationship suggests that total RNA dosed may be a key driver for a pharmacodynamic. This motivated us to analyze the data based on three groups of total milligrams of RNA dose. On the subsequent slide, the data for PCSK9 and LDL is presented according to these three ranges, less than 25 milligrams, 25 to 50 milligrams and 50 to 60 milligrams. Shown here is the PCSK9 reduction across the three total RNA dose groups and the yellow horizontal bar marks our Phase I goal. We saw a strong dose response between total RNA dose group and degree of PCSK9 reduction. In the highest total milligram RNA dose group, those who received 50 to 60 milligrams, we observed a mean 65% reduction of the blood PCSK9 protein. Shown here is the LDL reduction across the three total RNA dose groups. Once again, the yellow horizontal bar marks our Phase I goal. Similarly, we saw a strong response between total RNA dose group and degree of LDL reduction. In the highest total milligram RNA dose group, we observed a mean 59% reduction for LDL. Though based on a small sample in this Phase I trial, this level of LDL reduction achieved by VERVE-102 would be competitive with the most potent agents on the market. Importantly, every participant in the highest total RNA dose group achieved greater than 50% LDL reduction. As I mentioned earlier, the maximum reduction observed so far across the 14 participants was 69% LDL reduction, a participant in this 50 to 60-milligram RNA group. Given that LDL is a clinically relevant FDA-validated registration endpoint at total RNA doses above 50 milligrams, it is encouraging to see this level of consistency in the LDL reduction. Additionally, we noted that in the highest dose grouping, a mean of 55 milligrams of total RNA dose translated to a mean LDL reduction of 59%. This mean of 55 milligrams fixed dose of RNA aligns well with fixed doses that peer companies have progressed to pivotal studies. Here are the takeaways from the Heart-2 clinical trial to-date. VERVE-102 was well tolerated at all dose levels, demonstrating a very favorable safety profile of our proprietary GalNAc-LNP delivery platform. There were no treatment-related serious adverse events, no clinically significant laboratory abnormalities and no cardiovascular events. There was only one infusion-related reaction among the 14 treated participants. We observed a strong dose response with total RNA administered, which is emerging as a key driver of pharmacodynamic effect. At doses of greater than 50 milligrams, each participant experienced a greater than 50% lowering of LDL with a mean reduction of 59% and a maximum reduction of 69%. With that, I will hand it back over to Sek for closing remarks.

Thank you, Scott. This morning, we've shared a very promising product profile for VERVE-102, favorable clinical and laboratory safety as well as significant LDL reduction. Here are the emerging answers to each of the three questions posed earlier. First, we've seen excellent safety for VERVE-102 across the first 14 participants. Our proprietary GalNAc-LNP platform is showing a potentially best-in-class safety profile. Second, an RNA doses of 50 milligrams or more of VERVE-102, each participant achieved greater than 50% LDL reduction with a mean of 59% and a maximum of 69% observed so far. And lastly, our data demonstrated the durability of the base editing mechanism after 24 months so far with follow-up ongoing. Let's take a look now at the exciting year ahead for Verve. First, dosing is ongoing in the fourth dose cohort of 0.7 mg per kg. As of April 7, 2025, Verve has dosed two participants at 0.7 mg per kg. Early laboratory and clinical safety profile is in line with the first three cohorts. PD data are pending. We also plan to disclose final data from the dose escalation portion of the Heart-2 clinical trial in the second half of 2025. This release will include durability data for VERVE-102 that is currently being collected. We plan to submit an opt-in package to Eli Lilly in the second half of 2025 and expect a decision from Lilly by the end of the year. And finally, we expect to dose the first patient in the Phase II trial of VERVE-102 in the second half of 2025. Beyond these data, the VERVE-102 program is poised for success. Let's discuss four dimensions: time to market, capital, manufacturing and commercial. First, with respect to time to market, Phase I enrollment pace has exceeded expectations. We're poised for a rapid Phase II initiation and expect to dose the first patient by the end of the year. With 5 CTAs and the U.S. IND, we have expanded the global footprint for Phase 2 and onwards. We're pleased to have recently received FDA's Fast Track designation for VERVE-102. Fast Track is a process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical disease. Second, we're well capitalized with $524 million in cash as of the end of 2024 with runway into mid-2027. This is sufficient capital to support completion of the Phase II trial. And note that this runway projection does not currently include any cost sharing with an opt-in from Eli Lilly. And an opt-in would extend the runway even further. Third, we've established consistent drug supply for Phase 1 and are well equipped for our Phase II. Importantly, this type of product, RNA packaged in a lipid nanoparticle, has historically had a low cost of goods at scale and therefore, could support a range of price points. Finally, as you are aware, there is tremendous commercial potential for this asset. Sales worldwide for the PCSK9 class approached $4 billion in 2024 and have been growing at 40% year-over-year. In surveys of patients and health care providers, there had been strong enthusiasm for VERVE-102. If approved, surveyed cardiologists responded that they would prescribe VERVE-102 to 40% of their HeFH patients in the context of a future treatment landscape. I've spent the past 25 years caring for patients with heart disease and researching how to protect patients from it. This work has led to one core insight, if LDL levels are maintained really low lifelong, it's very hard to suffer a heart attack. We founded Verve in 2018 with a small team and a big idea, a one dose future to address cardiovascular disease. In 7 short years, our team has innovated to progress this stream from a concept through the clinic culminating in this first-in-human study for VERVE-102. The historic data presented today fuel our confidence in a future where a single infusion can lead to lifelong reduction of blood LDL cholesterol, delivering enduring efficacy for the millions of patients living with or at risk for ASCVD. With that, operator, please open the call for questions.

[Operator Instructions] Our first question coming from the line of Seamus Fernandez with Guggenheim.

So really, congratulations on the data. The safety, I think, is really unique and just exciting to see. Sek, I was just hoping that you might be able to put in context what these data mean for the rest of the portfolio and what you would hope to see given these data as we look forward to the VERVE-201 data. And then separately, as we kind of consider the Lilly opt-in dynamics, can you just remind us the structure of the agreement with Eli Lilly specifically around their -- should they opt-in the commitment to R&D, how that's structured as well as the rights that Verve holds consistent with the agreement?

Seamus, thank you so much for the kind words. We indeed are very excited by the emerging product profile for VERVE-102, be it safety as well as the efficacy. I'm joined today by Scott Vafai, our SVP of Clinical Development, as well as Allison Dorval, our CFO. I'm going to take the first part of your question, and then I'll turn it to Allison for the second part. In terms of the rest of the pipeline, as you know, we have a program against each of the three major cholesterol drivers of atherosclerosis. The one we talked about today was PCSK9 and focused on LDL. The other two carriers of cholesterol are triglyceride-rich lipoproteins and then lipoprotein(a). Our second and third programs address those two lipoproteins. The second program targets the gene ANGPTL3. Inactivation of ANGPTL3 will lower triglycerides but also LDL. That program is in the clinic, that's VERVE-201. And there should be really nice read-through from the VERVE-102 data we just showed you today to 201 because 201 shares the same base editor, the same GalNAc lipid nanoparticle delivery system that we just showed you today with the excellent safety. And then the main difference is just the guide. The guide for the 201 targets ANGPTL3, whereas the guide for 102 targets PCSK9. Now we started dosing patients with the 201 program in Q4 of '24 and we are dose escalating at present. And we are guiding to a program update by the end of the year, and that should be a data update based on enrollment. And so we're very excited about 201 and again, the read-through from 102 to that program. The third asset is lipoprotein(a). And this is an incredibly exciting target, a lot of interest in this area. Millions of patients with high Lp(a), at risk for heart attack and stroke as well as aortic stenosis. We have a onetime therapy that could permanently lower Lp(a) in preclinical development right now. That's in collaboration with Eli Lilly. It uses the same GalNAc-LNP delivery system. Again, there should be a nice read-through to that program. It does use a novel editor, one that we've developed internally for that program, and it reflects, I think, Verve's capabilities in innovating on delivery as well as editing and staying very product-focused. We're really focused on cardiovascular disease products and will -- and are technology-flexible, and we'll basically identify the right technology for each target and develop a bespoke product for each target. And that's what you're seeing happen with 102, 201 and 301. With that, let me turn it over to Allison Dorval who's going to walk you through our very exciting collaboration with Eli Lilly.

Thanks, Sek. Thanks for the question, Seamus. Maybe as a reminder, we do hold the majority rights for the collaboration with Lilly. We also control development, but more specifically, the way that the agreement works is that at the end of the Phase I trial after the last patient is dosed, we'll provide Lilly with an opt-in package. They've got some number of days to decide whether or not to opt in. Now assuming they do, assuming they do opt-in, they would begin to share in 1/3 of the worldwide development costs in exchange for 50% of our U.S. profit share. Importantly, we retain the other 50% of the U.S. rights as well as 100% of the ex-U.S. rights. So it really is a nice relationship where we've got the majority of control and rights when it comes to the development time line.

One more point to add there is just kind of thinking about how collaboratively we've been working with Lilly on the 102 product, we have a Joint Steering Committee that meets quarterly. We've been exploring different ideas for Phase 2 for the past 6 months or so and are really excited to continue to work with them as we move forward.

Our next question coming from the line of Kostas Biliouris with BMO Capital Markets.

Congrats on the impressive and better-than-expected data here. Two questions from us. The first one is in ORION trials, inclisiran achieved lower cholesterol reduction in heterozygous familial hypercholesterolemia patients than in ASCVD patients. So I'm wondering whether you saw any differences between the two populations that you enrolled in your trial, either on the safety or on the efficacy? And the second question is on Lilly collaboration, I'm wondering whether Lilly has seen the data that you presented today? And if so, do you happen to have any preliminary feedback from them? Congrats again.

Thank you, Kostas. In terms of HeFH versus ASCVD, yes, this trial included both sets of patients, 11 out of the 14 participants had HeFH, 3 with ASCVD. And as you mentioned, in ORION-9 and 10 and 11, they do see a difference. But actually, they're kind of the flip of what you said. They actually see lower LDL, so meaning about 40% LDL lowering compared to baseline in HeFH patients and about 50% in ASCVD patients. That's really what set the Phase I goal for us. You saw that in the slides, the yellow bar. We're looking to get about 40% to 50%. This trial is a majority HeFH. Despite that, we got a mean of 59% reduction in the 50 to 60-milligram RNA group. And so we're very excited that the profile that's emerging here looks very competitive with everything that's out there on the market. And if the 69% that we saw in maximum in one of the participants, if we continue to see that, this product could emerge as a best-in-class for the PCSK9 class. In terms of the second question, for Eli Lilly, they have actually seen the data, and they told us that they find the results very encouraging and are eager to receive the opt-in package from us in the second half of this year.

Our next question coming from the line of Roger Song with Jefferies.

Great. And my congratulations to the data. A couple of questions from us. The first one is why did you choose 0.7 as the fourth and maybe the highest dose cohort for your dose escalation study? And then also what would be the expectation goals for LDL-C reduction for that dose cohort? That's the first question. And then in terms of the FDA. What has been the interaction you have been having with the FDA? With this data and then potentially fourth dose cohort data, do you plan to apply BTD for 102?

I'll turn it over to Scott Vafai to answer the first two questions, and I'll take the FDA one. Go ahead, Scott.

Yes. So in terms of 0.7, really the goal with the dose escalation for us is to understand the dose response, identify an optimal dose from a safety and efficacy perspective. That dose escalation for us is guided by LDL as our primary biomarker, it's the clinically meaningful one, FDA-validated registration endpoint. And we're looking to find plateau for LDL reduction. Already at 0.6 and in that 50 to 60-milligram range, we're thrilled with what we're seeing for efficacy. In the 50 to 60-milligram range, seeing that 59% mean reduction and a maximum of 69%, so really dose escalating to 0.7 is to really make sure that we're finding the plateau for LDL reduction. But based on what we're seeing already, we think we're very close and really the remainder of the dose escalation is to just make sure that we're not leaving any efficacy on the table.

In terms of the interaction with the FDA. Yes, we -- as you have seen, over the last few weeks, we received IND clearance for VERVE-102. On Friday, we announced a Fast Track Designation that was awarded for VERVE-102. So despite all of the external news around the FDA, our interactions have been business as usual. We've had a very collaborative relationship with them, and we look forward to continuing that, particularly with this Fast Track Designation, which does allow for more communication, more direct communication with the agency moving forward. I think the Fast Track Designation is also typically awarded to products that really address a serious disease and address an unmet need and is I think a recognition of the unmet need that we're really focused on, which is enduring efficacy. So despite all the medicines that are available to lower cholesterol, there's still a huge unmet need, and that's really of enduring efficacy, and I think the FDA recognizes that with this Fast Track Designation.

Great. Maybe just if you can comment on the BTD potential.

What was the question, sorry? Yes. So we are planning to apply for breakthrough as well.

Our next question coming from the Andrea Newkirk with Goldman Sachs.

Congratulations here. Sek, if you could speak or maybe provide a little bit more color on your plans for the upcoming Phase II trial, what that design might look like? And then just remind us on your expectations on whether CVOT would be necessary to drive adoption or payer coverage.

Scott, why don't you take the Phase II and then I can talk about CVOT?

Yes. So the details around the Phase II are, of course, subject to regulatory interactions and approval. At this stage, we envision a Phase II study on the order of around 60 patients evaluating multiple fixed doses of VERVE-102.

Yes, probably, Andrea, 2 fixed doses, roughly 30 patients in each of the 2 dose levels, and we're guiding to a first patient dose by the end of the year and expect to carry out the Phase II in 2026. In terms of how we see the development progressing and particularly all the way to registration. For HeFH, Andrea, there's never been an outcomes trial required or performed. And so our base case expectation is the same development path as inclisiran, where there was a Phase II and then roughly a 500-person Phase III and both of those studies were LDL-based and the registration endpoint was LDL. And so that's really our base case. And you can see right now, inclisiran is on the market for both LDL and ASCVD -- sorry, both HeFH and ASCVD based on LDL studies, and inclisiran is expected to sell about $1 billion this year and is growing 100% year-over-year. And so we think that for this kind of product, LDL will be the registration endpoint for HeFH and that's really our base case.

Our next question coming from the line of Myles Minter with William Blair.

Congrats on the exciting data. I wanted to start with just where you and Lilly actually see VERVE-102 sitting within the PCSK9 inhibitor treatment landscape. Obviously, a crowded market. I get a lot of questions on how your efficacy is stacking up against the antibodies, 50% to 60% reduction every 2 weeks or monthly there. You've got inclisiran, obviously, 40% to 50%, depending on the population every 6 months and then some emerging data obviously coming from the oral inhibitors, I think 50% to 60% might be some food effects in there and they're once-daily. So just wondering how you're going to fit into that landscape there especially considering your comment that inclisiran is growing at 100%. That's the fastest-growing category there, and it's got the lowest LDL-C reduction. So just curious as to the dynamics. And the second question is just there was a variety of statin used in the trial. Just wondering whether the intensity of that changed throughout.

Thank you very much, Myles. Yes, in terms of the future treatment landscape, we see a landscape exactly as you described, of daily pills, twice a month injection, twice a year injection and one dose option. And why do we need the one dose option? As we described in the presentation, all the prior options, all the currently available options, they have some limitations, right, which really have to do with the fact that you can get one point, a single time point reduction of 40%, 50%, 60%, but that's not sustained due to the discontinuation rates. So as I -- as we talked about in the presentation, the real-world efficacy seen with these agents is not the label 40% to 60% because of the significant discontinuation rates for pills, twice a month injection and twice a year injections. Even at 1 year, the real-world efficacy is actually like 25% to 35% LDL lowering, right? And so what we need is a new option that actually gets patients' LDL down and keeps it down for a long time because that's what will drive reduction in heart attacks. And that's what we're hoping to offer, basically a new option that will actually provide enduring efficacy. Now what might the uptake be for this option? Is there interest? Is there appetite for this? We've actually asked cardiologists in the United States for that and we've actually asked patients as well. And let me walk you through the results from those two patient demand and physician demand surveys. In terms of -- we've surveyed 100 U.S. cardiologists in Q4 of '24 and presented to them a future treatment landscape of a daily PCSK9 pill, twice a month injection, twice a year injection and a onetime gene editing option and asked, for your next HeFH patients, which of those 4 options would you prefer. For their HeFH patients, for 40% of their HeFH patients, they prefer a one-and-done option, a one dose option. For ASCVD, they actually -- patients, they actually prefer for 20% of them. So there is really a lot of interest among physicians for this idea because they recognize how hard it is for patients to continue on therapy and significant discontinuation rates and the impact that it has on efficacy. And so they're really excited about this one dose idea. In terms of the patients, again, there was a third-party survey of patients with high cholesterol or a history of heart attack who have presented the same options in terms of daily pill, twice a year, twice a month injection, onetime option. And about 1/3 of patients preferred a one dose that would lead to potentially lifelong cholesterol reduction. And so there's room in this future treatment landscape for this kind of possibility. Now getting back to the inclisiran growth and the overall class probably expected to sell about $5 billion this year. That just reflects the large number of patients out there. But believe it or not, that $5 billion in sales expected this year is based on less than roughly 20% penetration in HeFH patients and less than 5% penetration among ASCVD. So there's still a huge amount of white space out there for additional treatment options that can solve the unmet need of enduring efficacy.

And then quickly on the statin intensity and if that changed over the trial at all.

Yes. So with regards to statin use, so participants are required to come into the study on stable statin and other lipid lowering therapy, and they're not allowed to change those therapies during the course of the trial.

Our next question coming from the line of Eric Joseph with JPMorgan.

Congrats on these data. Just a couple from us. One on treatment-related AEs. Can you talk about sort of how they are funding in relation to total mRNA administered? And then Secondly, as it relates to the 0.7 mg per kg cohort underway, I wonder whether this may also be an opportunity to kind of expand on what dosing to some extent. I guess how are you thinking about what total -- the average total mRNA administered would be in the patients being assessed in this cohort?

Thank you, Eric. I'll let Scott take these two questions, and starting with the AEs.

Yes. I think with regards to treatment-related emergent adverse events, we had one grade 2 infusion-related reaction, which we described, which occurred at 0.6. This was a transient event, very mild symptoms. The patient was given acetaminophen for comfort, which is what caused that to be considered grade 2. And the remainder of the related adverse events have all been grade 1. There have been no trends emerging or concerning treatment-related adverse events. And then at the 0.7 milligram per kilogram cohort, we've enrolled two patients, the early safety is in line with what we reported in the 14 participants reported today. That 0.7 allows us to dose up to 70 milligrams. The enrollment is ongoing for that, so we can't yet comment on average dose level for that group.

Yes. I think the way to think about it, though, on the x-axis of that graph that we showed, the dot plot, that was total RNA dose, on the y-axis is a percentage reduction and you saw this beautiful linear relationship between RNA dose and LDL reduction, a straight line down essentially. What we're looking to do is to see where does it plateau. What the 0.7 mg per kg cohort will allow us to do is explore the 60 to 70-milligram on the x-axis, that space. And that's what we're looking to do with this next dose level and then see where the relationship might plateau. And this will guide us in terms of picking probably two fixed doses to take forward to the Phase II. And as we said earlier, we are guiding to first patient dose in the Phase II by the end of the year.

It's very helpful. Maybe just one quick one, if I could, on just the Lilly collaboration and potential opt-in. Are there direct milestone payments to Verve associated with an opt-in? Or is it just cost offsets on further development that we should be thinking about here in the models?

Thanks, Eric. No, the way that the agreement works is when they opt in, they will begin sharing in those development costs. There's no opt-in payment to us at that time.

Our next question coming from the line of Whitney Ijem with Canaccord Genuity.

Adding my congrats on the data. A couple of follow-up questions. So just first on the physician survey work, when docs saying 40% and 20% of their patients in the different indications, is there any more color you have and you can share on what the profile of those patients were? Is it patients who tried other things and then noncompliant or younger patients or just any color there?

Yes, Whitney, thank you. It really is the patients that -- who's going to really derive benefit from decades of LDL lowering, right? Those are patients who really would have had a heart attack at a young age, and that's the reason we chose premature coronary disease patients for this Phase I. In addition, it's the patients with HeFH. Basically, they have a genetic condition, high cholesterol, often the first presenting symptom is heart attack. The patient that we showed you from 101 that is a heart attack before the age of 30, already had an LAD stent and is requiring kind of decades of LDL lowering. And you saw that patient has had 2 years of durability after the single infusion. So these are the patients that the cardiologists described to us as might be early adopters for this kind of technology. Now both of these groups, HeFH and premature CAD, these are unfortunately not small patient populations. There are about 3 million patients in U.S. and European Union with HeFH and about 20% of all ASCVD patients meet the premature criteria of men less than 55, women less than 65 that we've used. So it's really younger patients, patients with genetic disease. Those are the ones that I think cardiologists would initially focus on for this kind of product.

Got it. That's helpful. Then just on the Phase II design, you mentioned that via the steering committee with Lilly, you've had ongoing conversations but you've talked kind of about some of the design parameters of that study. So are there ongoing conversations still to be had? Or can you give us color on what those conversations have been? Or is the Phase II pretty settled at this point?

The Phase II design is pretty settled. We've had very productive, collaborative discussions with Lilly over the last 6 months or so, getting their input. And as -- but as Allison mentioned, ultimately, the development decisions rest with Verve. And so we've moved forward in terms of the Phase II protocol and are guiding to a first patient dose by the end of the year.

Our next question coming from the line of Rick Bienkowski with Cantor Fitzgerald.

Congrats on the impressive data set. My first question, I was hoping to get a little more color on the baseline characteristics of the 4 patients who were treated in the high-dose 0.6 mg per kg arm. Specifically, do you know what proportion of these patients in the cohort had HeFH and how many were on maximally tolerated statins at baseline? And my second question, the analysis of total RNA does make a pretty strong case for bringing forward fixed doses of VERVE-102 into later trials. So if you could just share your thoughts on potentially switching over to a fixed dose and if this could happen as early as the Phase II trial.

So in the 0.6 milligram per kilogram dose group, 3 out of the 4 patients had heterozygous FH. And yes, overall, the majority of patients in the trial were on -- were treated with high intensity of statin therapy. And in terms of the fixed dosing, we've also been very compelled by that relationship between total milligrams of RNA dosed and the LDL reduction. We are planning to move forward with fixed doses in the Phase II, but we will be finishing out the dose escalation using milligram per kilogram dosing.

Our next question coming from the line of Luca Issi with RBC Capital Markets.

Great. Congrats on the data. Maybe Sek and Allison just one more maybe on Eli Lilly. Can you just maybe expand a little bit more on what was the target product profile that they were looking for when they signed a deal a couple of years ago, and what gives you confidence that this data actually meets that bar? And then maybe related to it, is there any chance that you can renegotiate that deal so maybe they can be responsible for more than 1/3 of the development cost for maybe either higher U.S. economics or maybe ex-U.S. rights? Like any color there will be much appreciated. And maybe second, quickly, now that you also have materially derisked your lipid nanoparticle GalNAc formulation, can you talk about business development there?

Yes. Thank you, Luca. I'll have Allison take the second and third questions. Maybe I'll start with the target product profile in terms of what we've put forward and what Lilly's interest. So let me just take a moment to actually review the product profile that's emerging for VERVE-102, a onetime IV infusion with excellent safety, leading to a mean LDL reduction of nearly 60%, a max of nearly 70% so far and consistent reductions with each patient getting greater than 50%. And then the durability of the reduction for the mechanism out to 2 years plus and probably lifelong. So that profile, that's a home run. That is going to be best-in-class. That's way better than what we actually even set out to for our TPP. And I'm confident as this product profile holds up, it's really what a partner like Eli Lilly would be looking for as well.

And I'll take the next two questions. Luca, I think it's a great question about how we can leverage that relationship with Lilly. And I think the important part to note is that we've got the majority of those right in the agreement. And so I do think that there's opportunity to renegotiate. There's meaningful rights with ex U.S., for instance, that we could potentially think about moving around ownership of. Nothing in progress right now, but always something that we're thinking about. And then as far as other BD, I think that's a great question with our GalNAc-LNP, as Sek and Scott talked about, showing a potential best-in-class performance, we do think that, that could be something that we could potentially outlicense to others as well as thinking through these rights with our other program. So thank you.

Our next question coming from the line of Cory Jubinville with LifeSci Capital.

Congrats on these data and really impressive safety profile. Sek and Scott, can you just dig a little bit deeper into some of the baseline characteristics of the patients enrolled in Heart-2? We're seeing this remarkably clean safety profile as it relates to ALTs, platelets. But how much of the difference in safety that we're seeing with VERVE-102 versus 101 do you directly attribute to that change in the ionizable lipid as opposed to the enrolled patient population, seems to be quite a bit more stable than the rather severe group that was enrolled in Heart-1. And as a follow-up, I know metabolic syndrome is generally less common in HeFH versus pre-CAD patients. But can you comment on whether you enrolled any patients with baseline metabolic dysfunction, type 2 diabetes, NAFL, NASH, who might be more sensitive to LFT perturbations. And if so, how did those patients specifically respond to VERVE-102?

Yes. Thank you, Cory. I'll take the first, and then maybe, Scott, you take a second on the metabolic. Yes, in terms of thinking about the patient population, the safety here really pretty clear to us that it's the switching of the -- switch out of the LNP. So 101 versus 102, the GalNAc-LNP we're using here has a new ionizable lipid, has a different peg lipid and has the GalNAc added to it. In our preclinical data that we generated this past year as well as these clinical data, it's pretty clear that it's the LNP switch that has led to this remarkable difference in safety profile between the two products and not anything to do with the patient population. This patient population that we've enrolled here for Heart-2 is not -- cannot be characterized as mild. 10 out of the 14 patients have established ASCVD. If you look at the mean LDL in ORION-9, it's pretty similar to the mean LDL that we have here. And so this is very representative of premature CAD in HeFH patients. And really, again, the switch out of the LNP is almost certainly responsible for the improved safety profile. In terms of metabolic disease, Scott?

Yes. So the patient population did include patients with type 2 diabetes, obesity, hepatic steatosis. So we had a good representative mix and we're thrilled with the hepatic safety that we're seeing overall. Very limited numbers, but we're not seeing any of these factors have an influence at this stage.

Got it. That's helpful. And one last follow-up on safety. So in your conversations with the FDA, I know it's still early, but has there been any discussions with the agency pertaining to what they might be looking for in terms of the size or duration of a safety database that might support registration? Should we kind of be anticipating something similar to inclisiran there? Or is the agency approaching this differently given the one-and-done profile?

Yes. I think at this point, probably I can't comment on those regulatory interactions right now, but it's a good question you ask.

Now last question in queue coming from the line of Mitchell Kapoor with H.C. Wainwright.

Team, congrats on the data. First question, I wanted to ask about the baseline LDL, and if you can comment on any meaningful differences between the three dose groups. Can you just context -- could you just provide a little context for the reductions in LDL across those groups as it relates to the baseline LDL?

The baseline LDLs, as we said overall, is 140-milligram deciliter. This is a very strong product profile where you're seeing based on the RNA dose, a very striking reduction in LDL, and really speaks to, I think, the mechanism of action here of turning off the PCSK9 gene and leading to reductions in LDL. I think the baseline LDL in some studies has an impact on the percentage reduction. But here, it's pretty clear that this is really a mechanism of action and we're getting very strong reductions.

Okay. And then secondly, could you talk about how many patients we could see at the fourth dose level later this year? And then given the weight distribution you've seen for patients overall coming on to study, could we see potentially some data points beyond that 60-milligram fixed dose level?

Yes. So the cohorts are flexible. We enroll a minimum of three participants but can expand. The weight distribution we've seen so far has been around 60 kilos to up to 100 kilos. So the 0.7 milligram per kilogram dose level allows us to dose up to 70 milligrams.

And I'm showing no questions at this time. I will now turn the call back over to Dr. Kathiresan for any closing remarks.

Well, thank you all. Really exciting and historic day for us, and I think, hopefully, for the cardiovascular disease field. I want to leave with maybe a couple of thoughts. We talked a little bit about the emerging product profile and why we -- for VERVE-102 and why we find it so exciting. But I think there's another important question that we get asked, can Verve as a small biotech get this product ultimately to patients. And so there are really four items, I think, that give us confidence that we will get there. And number one is that with this data set, we've really derisked the product and the portfolio. This readout bend the probability of success curve far more than a typical Phase I data set, given the mechanism and the Phase I design. Second, we've got a clear path forward, and we're well financed to execute on it. The decisiveness of the data gives us clarity on the path forward. And with our current capital position allows us to progress VERVE-102 through a critical end of Phase II inflection. Third, we're excited, really excited about the collaboration with Eli Lilly. Lilly is encouraged by what they saw and we look forward to collaboratively working with them to advance development and share costs upon opt-in. And then lastly, this is a new story. It's an entire new way to treat chronic disease and so the old commercial analogs for gene therapy and gene editing just simply don't apply to this kind of situation. Here, the patient numbers and the scale of unmet needs are very large. But uniquely, the scale of product production can match that unmet need at cost of manufacturing that are very manageable. So this is really a new story. And I think people are going to have to start thinking about this very differently than the old models. So we as a team are super excited to pioneer a one-dose future for chronic disease. Thank you.

This concludes today's conference call. Thank you for participating, and you may now disconnect.