Interim phase 1 results of VERVE-102 for in vivo PCSK9 base editing

In an interim analysis of the phase 1 Heart-2 study, a single infusion of the investigational PCSK9 base-editing therapy VERVE-102 resulted in dose-dependent, substantial, and sustained reductions in PCSK9 and LDL-c levels.

This summary is based on the publication of Vafai SB, Täubel J, Ashdown T, et al. - In Vivo Base Editing of PCSK9 with VERVE-102 for Hypercholesterolemia. N Engl J Med. 2026 May 25. [Online ahead of print]. doi: 10.1056/NEJMoa2601283.

Introduction and methods

Background

Loss-of-function variants in PCSK9 are associated with lifelong reductions in LDL-c levels and a lower risk of ASCVD [1-3]. VERVE-102 is an investigational in vivo adenine base-editing therapy designed to durably inactivate PCSK9 in hepatocytes after a single intravenous infusion, potentially overcoming limitations of chronic lipid-lowering therapy related to long-term treatment adherence.

Aim of the study

The aim of the study was to evaluate the safety and efficacy of a single dose of VERVE-102 in patients with heterozygous familial hypercholesterolemia (HeFH) or premature coronary artery disease (CAD).

Methods

Heart-2 is an ongoing phase 1, open-label, single-ascending-dose study. A total of 35 adults (mean age was 52 years and 69% were men) with HeFH or premature CAD and a fasting LDL-c level ≥70 mg/dL (1.8 mmol/L) despite maximally tolerated lipid-lowering therapy received a single intravenous infusion of VERVE-102 at doses ranging from 0.3 to 1.0 mg/kg. Participants were followed for at least 28 days, with follow-up extending to 18 months. The median follow-up period was approximately 9 months.

Outcomes

The primary objective was safety; secondary objectives included changes in circulating PCSK9 and LDL-c levels.

Main results

Safety

• No dose-limiting toxicities or deaths occurred.
• Mild-to-moderate infusion-related reactions occurred in 7 participants (20%) and resolved with or without symptomatic treatment.
• Transient, asymptomatic alanine aminotransferase elevations (<2.5× the upper limit of normal) were observed in 3 patients.
• One participant developed aspiration pneumonitis, which was considered unrelated to VERVE-102.

Pharmacodynamics and durability

• Mean reductions in circulating PCSK9 levels were dose dependent, ranging from 51% at the 0.3-mg/kg dose to 88% at the 1.0-mg/kg dose.
• VERVE-102 lowered LDL-c in a dose-dependent manner, with mean reductions ranging from 9% to 62%. At the highest dose of 1.0-mg/kg, the mean absolute LDL-c reduction was 78 mg/dL (2.0 mmol/L).
• 15 of the 35 participants had at least 1 year of follow-up, and reductions in PCSK9 and LDL-c appeared durable throughout the available follow-up period.

Conclusion

In this interim analysis of the phase 1 Heart-2 study, a single infusion of the investigational base-editing therapy VERVE-102 resulted in dose-dependent, substantial, and sustained reductions in PCSK9 and LDL-c levels, with an acceptable short-term safety profile.

Find this article online at N Engl J Med.

References

1. Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 2005; 37: 161-5
2. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006; 354: 1264-72.
3. Zhao Z, Tuakli-Wosornu Y, Lagace TA, et al. Molecular characterization of loss of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 2006; 79: 514-23.