In Vivo Base Editing of PCSK9 with VERVE-102 for Hypercholesterolemia | New England Journal of Medicine

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Abstract<br>Background<br>Persons carrying loss-of-function variants of proprotein convertase subtilisin–kexin type 9 (PCSK9) have reduced levels of low-density lipoprotein (LDL) cholesterol and fewer atherosclerotic cardiovascular disease events than persons without such variants. VERVE-102 is an investigational base-editing therapy designed to durably inactivate PCSK9 in the liver.

Methods<br>In this phase 1, open-label, single-ascending-dose study, we administered 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]) to adults with heterozygous familial hypercholesterolemia or premature coronary artery disease. VERVE-102 consists of a messenger RNA encoding an adenine base-editor protein and a guide RNA targeting PCSK9, which are encapsulated in a lipid nanoparticle incorporating N-acetylgalactosamine. The objectives were to assess safety and changes in blood PCSK9 protein and LDL cholesterol levels.

Results<br>A total of 35 participants across the six dose cohorts received VERVE-102 and had at least 28 days of follow-up. No dose-limiting toxic effects occurred. Mild-to-moderate infusion-related reactions and transient elevations in alanine aminotransferase levels were observed. Aspiration pneumonitis occurred in a participant with gastroesophageal reflux disease. Dose-dependent mean reductions in the PCSK9 level ranged from 51% at the 0.3-mg-per-kilogram dose to 88% at the 1.0-mg-per-kilogram dose. Corresponding reductions in the LDL cholesterol level ranged from 9% at the 0.3-mg-per-kilogram dose to 62% at the 1.0-mg-per-kilogram dose, with an absolute reduction of 78 mg per deciliter at the highest dose. Reductions appeared to be durable throughout follow-up, which was at least 1 year in 15 participants.

Conclusions<br>One dose of VERVE-102 led to dose-dependent, substantial, and sustained reductions in PCSK9 and LDL cholesterol levels. (Funded by Verve Therapeutics; ClinicalTrials.gov number, NCT06164730.)

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Notes<br>This article was published on May 25, 2026, at NEJM.org.<br>A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.<br>Supported by Verve Therapeutics, a wholly owned subsidiary of Eli Lilly.<br>Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.<br>We thank the study participants, the staff members at the study sites, the data and safety monitoring board, and Dr. Marc P. Bonaca, Colorado Prevention Center and University of Colorado Anschutz.

Supplementary Material<br>Protocol (nejmoa2601283_protocol.pdf)<br>Download<br>5.77 MB

Supplementary Appendix (nejmoa2601283_appendix.pdf)<br>Download<br>1.15 MB

Disclosure Forms (nejmoa2601283_disclosures.pdf)<br>Download<br>14.19 KB

Data Sharing Statement (nejmoa2601283_data-sharing.pdf)<br>Download<br>90.05 KB

Information<br>Published In<br>New England Journal of Medicine<br>Recently Published

Copyright<br>Copyright © 2026 Massachusetts Medical Society. All rights reserved.<br>For personal use only. Any commercial reuse of NEJM Group content requires permission.

History<br>Published online : May 25, 2026

Topics<br>Cardiology General

Genetics General

Authors<br>Affiliations<br>Scott B. Vafai, M.D.<br>Verve Therapeutics, a wholly owned subsidiary of Eli Lilly, Boston

Jörg Täubel, M.D.<br>Richmond Pharmacology, London<br>St. George’s University of London, London

Thomas Ashdown, M.B., Ch.B.<br>Richmond Pharmacology, London

Riyaz S. Patel, M.B., B.S., M.D.<br>Institute of Cardiovascular Science, University College London, London<br>Barts Health NHS Trust, London

Sadaf Diamondali, M.B., B.S.<br>Barts Health NHS Trust, London

Jaimini Cegla, M.B., B.S., Ph.D.<br>Imperial College London, London

Handrean Soran, M.D.<br>National Institute for Health and Care Research–Wellcome Trust Clinical Research Facility, Manchester University NHS Foundation Trust, Manchester, United Kingdom

Bilal Bashir, M.B., B.S.<br>National Institute for Health and Care Research–Wellcome Trust Clinical Research Facility, Manchester University NHS Foundation Trust, Manchester, United Kingdom

Alexander Abitbol, M.D. https://orcid.org/0000-0001-6830-3532<br>LMC Diabetes and Endocrinology, Toronto<br>Centricity Research, Toronto

Daniel Gaudet, M.D., Ph.D. https://orcid.org/0000-0002-5185-3666<br>Department of Medicine, Université de Montréal, Montreal<br>ECOGENE-21 Clinical Research Center, Chicoutimi, QC, Canada

Alex Lauzière, M.D.<br>Department of Medicine, Université de Montréal, Montreal<br>ECOGENE-21...