Phase 1/2 trial · N Engl J Med 2026
Heart-2 trial
In Vivo Base Editing of PCSK9 with VERVE-102 for Hypercholesterolemia.
The bottom line
A single intravenous dose of the base-editing drug VERVE-102 produced dose-dependent, durable reductions in PCSK9 and LDL cholesterol, with an acceptable early safety profile, in a small phase 1 trial.
Early safety/biomarker dataUS status: Investigational
At a glance
- Medicine
- VERVE-102 (mRNA encoding adenine base-editor protein plus guide RNA targeting PCSK9, encapsulated in a GalNAc-containing lipid nanoparticle), single IV infusion at one of six doses from 0.3 to 1.0 mg of total RNA per kilogram
- Compared with
- None (single-arm, dose-ascending; no placebo/active comparator)
- People
- 35
- Who took part
- Adults with heterozygous familial hypercholesterolemia or premature coronary artery disease
- Design
- phase 1, open-label, single-ascending-dose study
- Follow-up
- at least 28 days for all participants; at least 1 year in 15 participants
- Main question
- Safety and changes in blood PCSK9 protein and LDL cholesterol levels
Main result
No dose-limiting toxic effects occurred; dose-dependent mean reductions in PCSK9 ranged from 51% (0.3 mg/kg) to 88% (1.0 mg/kg), with corresponding LDL cholesterol reductions of 9% to 62% (78 mg/dL absolute reduction at the highest dose)
Effect on LDL cholesterol
Reductions in LDL cholesterol 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
Other results
Not reported
Safety
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.
In the trial's own words
“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.”
Quoted from the abstract of N Engl J Med 2026, checked word for word against PubMed. PubMed 42187087 · Full paper (DOI)
How this medicine works, where it stands and what it costs: VERVE-102
Common questions
What did the Heart-2 trial find?
A single intravenous dose of the base-editing drug VERVE-102 produced dose-dependent, durable reductions in PCSK9 and LDL cholesterol, with an acceptable early safety profile, in a small phase 1 trial.
Who was in Heart-2?
35 people. Adults with heterozygous familial hypercholesterolemia or premature coronary artery disease.
What was Heart-2's main result?
No dose-limiting toxic effects occurred; dose-dependent mean reductions in PCSK9 ranged from 51% (0.3 mg/kg) to 88% (1.0 mg/kg), with corresponding LDL cholesterol reductions of 9% to 62% (78 mg/dL absolute reduction at the highest dose)
How much did LDL cholesterol change in Heart-2?
Reductions in LDL cholesterol 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
Related trials
- Ference 2016 (2016)Genetic mimicry shows that lowering LDL cholesterol via PCSK9 variants protects against cardiovascular events about as much as HMGCR (statin-target) variants, but both are linked to a smaller, additive increase in diabetes risk.
- Cohen 2006 (2006)People who naturally carry LDL-lowering PCSK9 gene variants from birth have a dramatically lower lifetime risk of coronary heart disease, supporting that lowering LDL-C, even modestly, over a lifetime substantially cuts cardiovascular risk.
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