VERVE-102 Gene-Editing Therapy Shows Promise for Durable LDL Reduction: NEJM

A new study published in The New England Journal of Medicine showed that a single infusion of VERVE-102, a gene-editing treatment that targets liver proprotein convertase subtilisin-kexin type 9 (PCSK9) synthesis, may result in significant and potentially long-lasting LDL cholesterol reduction in individuals with heterozygous familial hypercholesterolemia (FH) and/or premature coronary artery disease.

The PCSK9 gene is permanently rendered inactive by VERVE-102, an experimental genetic medication that uses an adenine base editor administered via a liver-targeted lipid nanoparticle. A single infusion produced strong, dose-dependent decreases in circulating PCSK9 and low-density lipoprotein cholesterol, which was recently assessed in the Phase 1b Heart-2 trial. This provides a highly transformative therapeutic option for people with high-risk heterozygous familial hypercholesterolemia.

Adults with heterozygous familial hypercholesterolemia or premature coronary artery disease were given one intravenous infusion of VERVE-102 at one of six doses (ranging from 0.3 to 1.0 mg of total RNA per kilogram of body weight [mg per kilogram]) in this study. VERVE-102 is a lipid nanoparticle containing N-acetylgalactosamine that encapsulates a guide RNA that targets PCSK9 and a messenger RNA that codes for an adenine base-editor protein. Assessing safety and variations in blood PCSK9 protein and LDL cholesterol levels were the goals.

VERVE-102 was administered to 35 individuals in each of the six dosage groups, with at least 28 days of follow-up. There were no adverse consequences that were dose-limiting. 

There were brief increases in alanine aminotransferase levels and mild-to-moderate infusion-related responses. One individual with gastroesophageal reflux disease experienced aspiration pneumonitis.

The PCSK9 level showed dose-dependent mean decreases ranging from 51% at the 0.3 mg/kg dosage to 88% at the 1.0 mg/kg treatment.

At the highest dose, there was an absolute reduction of 78 mg per deciliter. Corresponding reductions in the LDL cholesterol level varied from 9% at the 0.3-mg-per-kilogram dose to 62% at the 1.0-mg-per-kilogram dose.

Over the course of the follow-up, which lasted at least a year for 15 individuals, reductions seemed to be persistent. Overall, PCSK9 and LDL cholesterol levels were significantly, persistently, and dosage-dependently reduced after a single dose of VERVE-102.

Reference:

Vafai, S. B., Täubel, J., Ashdown, T., Patel, R. S., Diamondali, S., Cegla, J., Soran, H., Bashir, B., Abitbol, A., Gaudet, D., Lauzière, A., Brunham, L. R., Newby, D. E., Nicholls, S. J., Scott, R. S., Kerr, J., Tardif, J.-C., Lunken, C., Humphries, S. E., … Kathiresan, S. (2026). In vivo base editing of PCSK9 with VERVE-102 for hypercholesterolemia. The New England Journal of Medicine, NEJMoa2601283. https://doi.org/10.1056/NEJMoa2601283