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VERVE-102

In Vivo Base Editing of PCSK9 with VERVE-102 for Hypercholesterolemia

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Year of Publication: 2026

Authors: Vafai SB, Täubel J, Ashdown T, ..., Kathiresan S.

Journal: New England Journal of Medicine

Citation: N Engl J Med 2026;395(7):648-659.

Link: https://doi.org/10.1056/nejmoa2601283

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

Baseline Characteristics

Mean Age (years): 52

Male n (%): 24 (69%)

Heterozygous FH n (%): 29 (83%)

HeFH with premature CAD n: 9

Premature CAD alone n (%): 6 (17%)

Mean baseline LDL-C (mg/dL): 129

Mean baseline LDL-C (mmol/L): 3.3

On statin therapy n (%): 32 (91%)

On high-intensity statin n (%): 25 (71%)

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
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(7):648-659.

Content summarized and formatted by NeuroTrials.ai.

VERVE-102

(2026)

Objective

To assess the safety and pharmacodynamic effects of VERVE-102, an in vivo base-editing therapy designed to durably inactivate PCSK9 in the liver, in adults with heterozygous familial hypercholesterolemia or premature coronary artery disease.

Study Summary

• No dose-limiting toxic effects; mild-to-moderate infusion-related reactions and transient ALT elevations observed
• Dose-dependent mean PCSK9 reductions: 51% at 0.3 mg/kg to 88% at 1.0 mg/kg
• Dose-dependent mean LDL cholesterol reductions: 9% at 0.3 mg/kg to 62% (absolute 78 mg/dL) at 1.0 mg/kg
• Reductions appeared durable throughout follow-up (at least 1 year in 15 participants)
• One case of aspiration pneumonitis in a participant with GERD

Intervention

Single intravenous infusion of VERVE-102 (mRNA encoding an adenine base-editor + guide RNA targeting PCSK9, encapsulated in a GalNAc-lipid nanoparticle) at one of six weight-based doses (0.3, 0.45, 0.6, 0.7, 0.8, or 1.0 mg total RNA/kg).

Inclusion Criteria

Adults 18-70 years with heterozygous familial hypercholesterolemia or premature coronary artery disease (≤55y men, ≤65y women), fasting LDL-C ≥70 mg/dL on maximum tolerated oral lipid-lowering therapy.

Study Design

Arms: VERVE-102 0.3 mg/kg (n=4) vs 0.45 mg/kg (n=6) vs 0.6 mg/kg (n=4) vs 0.7 mg/kg (n=8) vs 0.8 mg/kg (n=6) vs 1.0 mg/kg (n=7)

Patients per Arm: 0.3 mg/kg: 4; 0.45 mg/kg: 6; 0.6 mg/kg: 4; 0.7 mg/kg: 8; 0.8 mg/kg: 6; 1.0 mg/kg: 7

Outcome

• PCSK9 protein reduced 51% (0.3 mg/kg) to 88% (1.0 mg/kg) in a dose-dependent manner
• LDL cholesterol reduced 9% (0.3 mg/kg) to 62% (1.0 mg/kg); absolute reduction 78 mg/dL at highest dose
• Effects durable throughout at least 1 year of follow-up in 15 participants
• Safety: no dose-limiting toxicities; mild-moderate infusion reactions and transient ALT elevations; 1 case aspiration pneumonitis (GERD patient)

Bottom Line

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.

Study Design

Study Type: Phase 1, open-label, single-ascending-dose, first-in-human interim analysis (Heart-2)
Randomization: No
Blinding: Open-label
Sample Size: 35
Follow-up: At least 28 days per participant; ≥1 year in 15 participants; scheduled visits through day 365 with transition to long-term follow-up study
Countries: Australia, Canada, New Zealand, United Kingdom

Primary Outcome

Definition: 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

Control	Intervention	HR/OR	P-value
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	-

Limitations & 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

Citation

N Engl J Med 2026;395(7):648-659.

View Original Publication →

VERVE-102

In Vivo Base Editing of PCSK9 with VERVE-102 for Hypercholesterolemia

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Criticisms

Funding

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