VERVE-102 is an investigational in-vivo adenine base-editing therapy designed to reduce hepatic PCSK9 production after a single intravenous infusion. In the phase 1 Heart-2 study, 35 adults with heterozygous familial hypercholesterolaemia or premature coronary artery disease received one of six ascending doses from 0.3 to 1.0 mg/kg.
The primary objective was safety, with changes in circulating PCSK9 and fasting LDL cholesterol assessed as pharmacodynamic outcomes.
What did the study find?
The lipid-lowering effect increased overall with dose. At the highest dose of 1.0 mg/kg, mean time-averaged PCSK9 fell by 88% and LDL-C by 62%. Mean LDL-C decreased from 128 to 51 mg/dL, corresponding to an absolute reduction of 78 mg/dL.
| Dose | PCSK9 change | LDL-C change |
|---|---|---|
| 0.3 mg/kg | −51% | −9% |
| 0.45 mg/kg | −59% | −44% |
| 0.6 mg/kg | −61% | −45% |
| 0.7 mg/kg | −64% | −33% |
| 0.8 mg/kg | −77% | −51% |
| 1.0 mg/kg | −88% | −62% |
The LDL-C response was not perfectly linear across all cohorts, but the largest reductions were observed at the higher doses.
How durable was the effect?
Reductions in both PCSK9 and LDL-C appeared stable during follow-up. Fifteen participants had follow-up extending to at least one year, and the maximum available follow-up was 18 months.
These findings suggest a sustained pharmacodynamic effect, but they do not establish permanent LDL-C lowering.
What were the safety findings?
No dose-limiting toxic effects or deaths were reported. Infusion-related reactions occurred in seven participants and were all grade 1 or 2. Three participants developed transient asymptomatic ALT elevations of at least twice the upper limit of normal. One grade 3 aspiration pneumonitis event was judged unrelated to treatment.
The sample remains too small to define uncommon or delayed adverse effects, particularly those related to off-target or unintended genomic editing.
What does this mean for clinical practice?
This study provides early proof of concept that a single in-vivo PCSK9 base-editing infusion can produce substantial and apparently durable LDL-C lowering.
However, VERVE-102 remains investigational. The study was small, open-label and uncontrolled, and it was not designed to assess cardiovascular outcomes. Long-term safety, durability over many years and clinical benefit remain uncertain.
Clinical takeaway
VERVE-102 produced marked PCSK9 and LDL-C reductions after a single infusion, with the highest dose lowering mean LDL-C by 62% and effects appearing sustained beyond one year in available follow-up. These are promising phase 1 data, but they should not yet alter routine lipid-lowering practice.
Full reference
Vafai SB, Täubel J, Ashdown T, et al. In Vivo Base Editing of PCSK9 with VERVE-102 for Hypercholesterolemia. New England Journal of Medicine. 2026;395:648–659. doi:10.1056/NEJMoa2601283.