First-in-human trial results of PCSK9 gene editing therapy in HeFH and ASCVD

Safety and Pharmacodynamic Effects of VERVE-101, an Investigational DNA Base Editing Medicine Designed to Durably Inactivate the PCSK9 Gene and Lower LDL Cholesterol – Interim Results of the Phase 1b heart-1 Trial

News - Nov. 13, 2023

Presented at the AHA Scientific Sessions 2023 by: Andrew Bellinger, MD, PhD- Boston, MA, USA

Introduction and methods

Currently, most patients treated for heterozygous familial hypercholesterolemia (HeFH) do not achieve LDL-c targets. VERVE-101 is a novel CRISPR base editing therapy that inactivates the hepatic PCSK9 gene and thereby lowers LDL-c levels. The interim results from the first-in-human trial of VERVE-101 in patients with HeFH and established ASCVD were presented at the meeting.

The heart-1 trial is an ongoing, open-label, single-ascending dose, phase 1b study designed to assess the safety and tolerability of VERVE-101. The interim analysis included 10 adult HeFH patients with severe, advanced ASCVD and high CVD risk (both short-term and lifetime), and elevated LDL-c levels despite maximum-tolerated oral lipid-lowering therapy. After pre-medication with dexamethasone and antihistamines, a single dose of VERVE-101 was administered via peripheral intravenous infusion across 4 escalating-dose cohorts (0.1, 0.3, 0.45, and 0.6 mg/kg).

The primary endpoints were safety and tolerability. Additional endpoints were pharmacokinetics and percent change of blood levels of PCSK9 protein and LDL-c from baseline to 28 days.

Main results

  • At 28 days, the blood PCSK9 level was substantially lower compared with baseline in the higher dose cohorts. The 2 patients treated with VERVE-101 at a dose of 0.45 mg/kg showed a reduction of 59% and 84%, respectively, whereas the PCSK9 level reduced by 47% in the patient receiving the 0.6-mg/kg dose.
  • The blood LDL-c level at 28 days was decreased by 39% and 48% (0.45-mg/kg dose) and 55% (0.6-mg/kg dose).
  • In the single participant in the highest dose cohort, the 55%-reduction in LDL-c level was still present at 180 days.
  • Adverse events were observed in 6 patients, of whom 4 experienced an infusion-related reaction (all in 0.45- and 0.6-mg/kg dose cohorts).
  • Serious CV adverse events occurred in 2 patients, of whom 1 had an MI, which was deemed potentially related to the study treatment. According to the independent Data and Safety Monitoring Board, these CV events were consistent with a severe, advanced ASCVD patient population, and it therefore recommended continuing the trial.


Administration of VERVE-101 resulted in dose-dependent reductions in blood levels of PCSK9 (up to 84%) and LDL-c (up to 55%) in 10 HeFH patients with ASCVD and uncontrolled hypercholesterolemia. The safety profile supported continued development of the therapeutic agent.

More patients are to be enrolled in the 0.45- and 0.6-mg/kg dose cohorts. The investigators plan to conduct a placebo-controlled phase 2 RCT with VERVE-101 in 2025.

- Our reporting is based on the information provided at the AHA Scientific Sessions 2023 -

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