N Engl J Med
Gene editing cut LDL-C by more than half in early trial
Clinical takeaway: This hints at a potential shift from chronic management to one-time treatment. FDA has granted Fast Track designation for VERVE-102 to reduce LDL-C in patients with hyperlipidemia and high lifetime cardiovascular risk. A Phase 2 trial is slated to start before year-end.
Many patients with elevated LDL-C never reach target despite statins, ezetimibe, and injectable PCSK9 inhibitors, leaving them at sustained cardiovascular risk. Loss-of-function PCSK9 variants confer markedly lower lifetime coronary risk, raising the question of whether one-time gene editing could replicate that protection. The Phase 1 Heart-2 trial offers the first sustained clinical signal that it might.
VERVE-102 reduced LDL-C by 62% at the highest dose (1.0 mg/kg), an absolute drop of 78 mg/dL. The lowest dose (0.3 mg/kg) produced only a 9% reduction, while the four intermediate cohorts ranged from 33% to 51%. PCSK9 reductions climbed in a dose-dependent manner from 51% at the lowest dose to 88% at the highest.
The 62% LDL-C reduction is in line with what current PCSK9 inhibitors achieve with chronic dosing, which is about 40% to 60%. Effects were sustained over follow-up of up to 18 months, with 15 participants followed for at least a year.
Lilly plans to begin Phase 2 enrollment by the end of 2026. VERVE-102 uses a lipid nanoparticle to deliver messenger RNA encoding an adenine base editor and a guide RNA targeting PCSK9, producing a single permanent edit in hepatocytes.
Heart-2 is an open-label, single-ascending-dose study in 35 adults with heterozygous familial hypercholesterolemia or premature coronary artery disease who remain above LDL-C targets despite maximally tolerated oral therapy. No cardiovascular outcomes were measured. Participants will be followed for up to 15 years.
No dose-limiting toxicities or treatment-related serious adverse events occurred. Reported events linked to VERVE-102 were limited to mild-to-moderate infusion-related reactions (20% of participants) and transient, asymptomatic ALT elevations that resolved within a week. One grade 3 aspiration pneumonitis in a participant with GERD was deemed unrelated to treatment. The GalNAc-lipid nanoparticle formulation appears to have avoided the safety signals seen with the predecessor VERVE-101.
Existing PCSK9 inhibitors lower LDL-C but require ongoing administration, with discontinuation rates of 30% to 50% within a year of starting therapy. A single infusion that produces lifelong PCSK9 suppression would change management entirely, particularly for patients with familial hypercholesterolemia who face decades of treatment. The authors estimate the 78 mg/dL absolute reduction, if maintained over 20 years, would cut cardiovascular disease risk by more than half in most patients with hypercholesterolemia.
"The Heart-2 results provide early clinical evidence that a single dose of VERVE-102 may mimic the LDL-C lowering effects of PCSK9 cardioprotective variants, potentially transforming cardiovascular care from chronic management to a one-time treatment," said Sekar Kathiresan, MD, Lilly senior vice president and co-founder of Verve Therapeutics, which was acquired by Lilly last year for $1 billion.
Source: Vafai SB. N Engl J Med. 2026 May 25. In vivo base editing of PCSK9 with VERVE-102 for hypercholesterolemia