Heart-2: VERVE-102 Lowers LDL-C in Phase 1b Hypercholesterolemia Trial

A single infusion of VERVE-102, an investigational in vivo base-editing therapy targeting hepatic PCSK9, was associated with dose-dependent reductions in circulating PCSK9 and LDL-C in an interim analysis of the phase 1b Heart-2 trial, according to data announced by Eli Lilly and Company.¹

“These early data give us encouraging evidence that in vivo base editing of PCSK9 may offer a novel approach to achieving substantial and durable LDL-C reduction with a one-time treatment,” Riyaz Patel, MD, a cardiologist at Barts Health NHS Trust and professor of cardiology at University College London, said in the company announcement.

The findings, presented at the European Atherosclerosis Society Congress and described by Lilly as simultaneously published in The New England Journal of Medicine, represent early clinical evidence for a gene-editing approach intended to produce long-term LDL-C lowering after a single intravenous administration. The clinical relevance is greatest for patients with heterozygous familial hypercholesterolemia (HeFH) or premature coronary artery disease (CAD), groups in whom lifelong LDL-C exposure remains a major driver of atherosclerotic risk.

Heart-2 is an ongoing, open-label, single-ascending-dose phase 1b study evaluating the safety, tolerability, and pharmacodynamic effects of VERVE-102 in adults with HeFH or premature CAD who require additional LDL-C lowering despite maximally tolerated oral lipid-lowering therapy. The interim analysis included 35 participants treated across 6 dose cohorts: 0.3, 0.45, 0.6, 0.7, 0.8, and 1.0 mg/kg. All participants received a single intravenous infusion and completed the planned dose.

Mean reductions in PCSK9 ranged from 51% at the 0.3 mg/kg dose to 88% at the 1.0 mg/kg dose. Corresponding mean LDL-C reductions were 9%, 44%, 45%, 33%, 51%, and 62% across the 0.3-, 0.45-, 0.6-, 0.7-, 0.8-, and 1.0-mg/kg cohorts, respectively. Lilly reported that reductions were sustained over follow-up of up to 18 months; the median follow-up was approximately 9 months as of the February 27, 2026, data cutoff, and 15 participants had at least 1 year of follow-up.

Safety data were limited by the small sample size and early-phase design. Lilly reported no treatment-related serious adverse events and no dose-limiting toxicities. Adverse events attributed to VERVE-102 included low-grade infusion-related reactions and fatigue. No participants withdrew from the study.

VERVE-102 consists of messenger RNA encoding an adenine base editor and a guide RNA targeting PCSK9, both encapsulated in a lipid nanoparticle. The therapy is designed to edit PCSK9 in hepatocytes and thereby reduce PCSK9 protein production, a strategy intended to mimic naturally occurring loss-of-function PCSK9 variants. Such variants have been associated with lower LDL-C and reduced coronary heart disease risk in genetic studies.

Clinically, the program sits within a treatment landscape already shaped by intensive LDL-C lowering. Contemporary cholesterol guidance emphasizes high-intensity statin therapy as foundational treatment for patients at high atherosclerotic cardiovascular disease risk, with ezetimibe and PCSK9-targeting therapies added when LDL-C remains above threshold despite maximally tolerated statin therapy. However, adherence, access, injection burden, and the need for sustained treatment can limit real-world LDL-C control.

HeFH is characterized by lifelong LDL-C elevation and increased risk of premature atherosclerotic cardiovascular disease. Prevalence estimates vary by population, but contemporary data support that familial hypercholesterolemia is substantially underdiagnosed relative to expected population frequency. In Heart-2, premature CAD was defined as evidence of CAD occurring at age 55 years or younger in men or 65 years or younger in women.

The US Food and Drug Administration has granted Fast Track designation to VERVE-102 for reducing LDL-C in participants with hyperlipidemia and high lifetime cardiovascular risk, according to Lilly. The company said it plans to begin enrolling a phase 2 study by the end of 2026, and Heart-2 participants are expected to enter long-term follow-up for up to 15 years.

References

1. Eli Lilly and Company. A single dose of Lilly’s PCSK9 base editor, VERVE-102, reduced PCSK9 by up to 88% and LDL-C by up to 62%, with durable effects supporting its potential as a one-time treatment for hypercholesterolemia. Published May 25, 2026. Accessed May 26, 2026. https://investor.lilly.com/news-releases/news-release-details/single-dose-lillys-pcsk9-base-editor-verve-102-reduced-pcsk9-88

2. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-1272. doi:10.1056/NEJMoa054013

3. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC guideline on the management of blood cholesterol. Circulation. 2019;139(25):e1082-e1143. doi:10.1161/CIR.0000000000000625

4. Davletov K, et al. Prevalence of familial hypercholesterolemia and its association with cardiovascular risk in a cross-sectional adult population. J Clin Med. 2025;14(22):8213. doi:10.3390/jcm14228213