VERVE-102
In Vivo Base Editing of PCSK9 with VERVE-102 for Hypercholesterolemia
Clinical Question
Can a single infusion of an in vivo adenine base-editing therapy targeting PCSK9 safely and durably lower LDL cholesterol in patients with heterozygous familial hypercholesterolemia or premature coronary artery disease?
Bottom Line
In this phase 1 interim analysis (Heart-2), a single infusion of VERVE-102 produced dose-dependent, substantial (up to 88% PCSK9 and 62% LDL-C reductions), and durable (≥1 year) lowering of PCSK9 and LDL cholesterol without dose-limiting toxic effects, supporting further development of one-time in vivo base editing as an alternative to chronic lipid-lowering therapy.
Major Points
- First reported clinical data of a GalNAc-lipid nanoparticle-delivered adenine base-editing therapy targeting PCSK9 in humans.
- Dose-dependent mean PCSK9 protein reduction: 51% (0.3 mg/kg) to 88% (1.0 mg/kg).
- Dose-dependent mean LDL-C reduction: 9% (0.3 mg/kg) to 62% (1.0 mg/kg); absolute 78 mg/dL at the highest dose.
- Effect appeared durable throughout follow-up, with ≥1 year of follow-up in 15 participants.
- No dose-limiting toxicities; mild-to-moderate infusion-related reactions and transient ALT elevations observed; one aspiration pneumonitis in a participant with GERD.
- Supports a paradigm shift toward one-time genome-editing therapy for lifelong LDL-C reduction.
Design
Study Type: Phase 1, open-label, single-ascending-dose, first-in-human interim analysis (Heart-2)
Randomization:
Blinding: Open-label
Allocation: Sequential dose-escalation cohorts
Follow-up Duration: At least 28 days per participant; ≥1 year in 15 participants; scheduled visits through day 365 with transition to long-term follow-up study
Centers: 0
Countries: Australia, Canada, New Zealand, United Kingdom
Sample Size: 35
Analyzed: 35
Analysis: Pharmacodynamic data reported as time-averaged values from day 28 through last follow-up using trapezoidal-rule area-under-the-curve analysis
Registration: NCT06164730
Inclusion Criteria
- Adults 18-70 years of age
- Diagnosis of heterozygous familial hypercholesterolemia OR premature coronary artery disease (≤55 years in men, ≤65 years in women)
- Fasting LDL cholesterol ≥70 mg/dL (1.8 mmol/L) while on maximum tolerated dose of oral lipid-lowering therapy (statin with or without ezetimibe)
Exclusion Criteria
- Uncontrolled hypertension
- Inadequately controlled type 2 diabetes mellitus
- Ongoing use of a PCSK9 inhibitor treatment
Arms
| Field | VERVE-102 0.3 mg/kg | VERVE-102 0.45 mg/kg | VERVE-102 0.6 mg/kg | VERVE-102 0.7 mg/kg | VERVE-102 0.8 mg/kg | VERVE-102 1.0 mg/kg |
|---|---|---|---|---|---|---|
| N | 4 | 6 | 4 | 8 | 6 | 7 |
| Intervention | Single IV infusion of VERVE-102 at 0.3 mg total RNA/kg over up to ~4 hours; premedication with dexamethasone plus H1/H2 antihistamines | Single IV infusion of VERVE-102 at 0.45 mg total RNA/kg | Single IV infusion of VERVE-102 at 0.6 mg total RNA/kg | Single IV infusion of VERVE-102 at 0.7 mg total RNA/kg | Single IV infusion of VERVE-102 at 0.8 mg total RNA/kg | Single IV infusion of VERVE-102 at 1.0 mg total RNA/kg |
| Duration | Single dose | Single dose | Single dose | Single dose | Single dose | Single dose |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Safety of VERVE-102 (adverse events graded by CTCAE v5.0) with secondary pharmacodynamic assessment of percent and absolute change from baseline in plasma PCSK9 and fasting LDL cholesterol | Primary | N/A (no control arm) | Dose-dependent mean PCSK9 reduction: 51% (0.3 mg/kg) to 88% (1.0 mg/kg); dose-dependent mean LDL-C reduction: 9% (0.3 mg/kg) to 62% (1.0 mg/kg) with absolute reduction of 78 mg/dL at 1.0 mg/kg | Up to 88% PCSK9 reduction and 62% (78 mg/dL) LDL-C reduction at highest dose | |
| Durability of PCSK9 and LDL-C reductions | Secondary | Reductions appeared durable throughout follow-up, which was at least 1 year in 15 participants | |||
| Pharmacokinetics of VERVE-102 | Secondary | Characterized as a secondary objective; specific PK parameters not provided in the extracted text | |||
| Dose-limiting toxic effects | Safety | None observed | |||
| Infusion-related reactions | Safety | Mild-to-moderate | |||
| Alanine aminotransferase (ALT) elevations | Safety | Transient elevations observed | |||
| Aspiration pneumonitis | Safety | Occurred in one participant with gastroesophageal reflux disease | |||
| Dose-limiting toxic effects | Adverse | None | |||
| Infusion-related reactions | Adverse | Mild-to-moderate | |||
| ALT elevations | Adverse | Transient | |||
| Aspiration pneumonitis | Adverse | 1 participant (with GERD) | |||
Criticisms
- Small phase 1 open-label study without a control arm
- Interim analysis with limited long-term follow-up (≥1 year in only 15 of 35 participants) — durability beyond 1 year and long-term safety of irreversible genome editing remain unknown
- Sponsor (Verve Therapeutics/Eli Lilly) designed the study, analyzed the data, and wrote the first draft of the manuscript
- No hard cardiovascular outcome data
- Off-target editing and germline transmission assessed preclinically only
- Study population limited to select high-cardiovascular-risk phenotypes; excludes PCSK9-inhibitor users, uncontrolled hypertension, and uncontrolled T2DM
Funding
Verve Therapeutics (a wholly owned subsidiary of Eli Lilly)
Based on: VERVE-102 (New England Journal of Medicine, 2026)
Authors: Vafai SB, Täubel J, Ashdown T, ..., Kathiresan S.
Citation: N Engl J Med 2026;395:648-59.
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