Scott B. Vafai, Jörg Täubel, Thomas Ashdown, Riyaz S. Patel, Sadaf Diamondali, Jaimini Cegla, Handrean Soran, Bilal Bashir, Alexander Abitbol, D Gaudet, Alex Lauzière, Liam R. Brunham, David E. Newby, S Nicholls, Russell S. Scott, Jane Kerr, Jean-Claude Tardif, C. Lunken, Steve E. Humphries, Verena Karsten, Patrick D. Tyler, Xinyan Zhang, Nidal Huniti, Patrick A. Flight, Chelsey L. Jensen, Rick Falzone, Joseph C. Biedenkapp, Troy Lister, Leslie E. Stolz, Amit V. Khera, Sekar Kathiresan
BACKGROUND: in the liver. METHODS: -acetylgalactosamine. The objectives were to assess safety and changes in blood PCSK9 protein and LDL cholesterol levels. RESULTS: 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: 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.).