{"id":"a178b3b1594a","type":"article","url":"https://hartvaat.nl/2026/05/25/verve-102-eenmalige-base-editing-schakelt-pcsk9-blijvend-uit-fase-1/","title":"VERVE-102: eenmalige base-editing schakelt PCSK9 blijvend uit (fase 1)","title_en":"In Vivo Base Editing of PCSK9 with VERVE-102 for Hypercholesterolemia","category":"cholesterol","category_label":"Cholesterol","professions":["apotheker","cardioloog","internist"],"tags":["pcsk9-remmers","pcsk9-remmers-nieuwe-generatie"],"journal":"The New England journal of medicine","doi":"10.1056/NEJMoa2601283","source_url":"https://doi.org/10.1056/NEJMoa2601283","authors":["Scott B Vafai","Jörg Täubel","Thomas Ashdown","Riyaz S Patel","Sadaf Diamondali","Jaimini Cegla","Handrean Soran","Bilal Bashir","Alexander Abitbol","Daniel Gaudet","Alex Lauzière","Liam R Brunham","David E Newby","Stephen J Nicholls","Russell S Scott","Jane Kerr","Jean-Claude Tardif","Catherine 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"],"significance":9,"published":"2026-05-25","source_date":"2026-05-25","image":"","kennis":["https://hartvaat.nl/kennis/lipiden/lpa-meten-wanneer-waarom/","https://hartvaat.nl/kennis/lipiden/familiaire-hypercholesterolemie/"],"congress":"","summary_en":"VERVE-102 is a base-editing therapy that permanently inactivates the hepatic PCSK9 gene with a single infusion — an adenine base-editor mRNA plus a guide RNA in a GalNAc lipid nanoparticle. In this phase 1 study of 35 patients with heterozygous familial hypercholesterolaemia or premature coronary artery disease, PCSK9 protein fell dose-dependently by 51% to 88% and LDL cholesterol by up to 62%, with a durable effect after one dose. No dose-limiting toxic effects occurred; there were mild-to-moderate infusion reactions and transient ALT elevations (and one aspiration pneumonitis in a patient with reflux). A one-time, durable LDL reduction thus comes into view as a treatment concept.","created":"2026-07-03T10:32:16Z","updated":"2026-07-03T13:31:13Z","licence":"Citeer vrij, met bronvermelding en een link naar hartvaat.nl (de url van het record). Samenvattingen zijn redactioneel werk van HartVaat; de oorspronkelijke publicaties blijven van hun uitgevers (doi). Geen medisch advies.","body_markdown":"VERVE-102 is een base-editing-therapie die met één infuus het PCSK9-gen in de lever permanent inactiveert — een adenine-base-editor-mRNA plus een gids-RNA, verpakt in een GalNAc-lipidenanopartikel. In deze fase 1-studie bij 35 patiënten met heterozygote familiaire hypercholesterolemie of vroeg coronairlijden daalde het PCSK9-eiwit dosisafhankelijk met 51% tot 88% en het LDL-cholesterol tot 62%, met een blijvend effect na één toediening. Er traden geen dosislimiterende bijwerkingen op; wel milde tot matige infusiereacties en voorbijgaande ALAT-stijgingen (en bij één patiënt met reflux een aspiratiepneumonitis). Daarmee komt een eenmalige, blijvende LDL-verlaging als behandelconcept in beeld.","abstract_original":"BACKGROUND: 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: 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: 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.)."}