Phase 1b Trial Results Prove Safety, Tolerability of VERVE-101 Treatment in Patients with High-Risk HeFH


A single infusion of VERVE-101, a gene editing tool, improved both blood PCSK9 protein levels and blood LDL-C levels in 10 individuals with high-risk HeFH.

Initial results from the heart-1 trial, a first-in-human phase 1b trial, proved the safety and tolerability of VERVE-101, said cardiologist Andrew Bellinger, MD, chief scientific officer of Verve Therapeutics, during a session at the American Heart Association (AHA) Scientific Sessions 2023 in Philadelphia, Pennsylvania.

The heart-1 trial involved patients with high-risk heterozygous hypercholesterolemia (HeFH), established atherosclerotic cardiovascular disease (ASVCD) with severe elevations in lipoprotein-cholesterol (LDL-C). The enrolled patients received VERVE-101, a CRISPR base-editing medicine designed to deactivate the PCSK9 gene and lower LDL-C with a single DNA base pair change. Previously, a single infusion of VERVE-101 in non-human primates demonstrated to lower LDL-C for 2.5 years.

DNA editing

Image credit: phonlamaiphoto |

“Certain individuals carry gene variants that naturally turn off the PCSK9 gene. These individuals have lifelong low levels of blood LDL-C, and dramatic protection against ASCVD,” explained Bellinger during the session. “And now with PCSK9 inhibitors, there is pharmacologic validation of the target. These observations led us at first to hypothesize [if we] can we develop a single-course treatment that mimics the natural PCSK9 variants, which directly lower LDL-C and protecting instead against ASVCD.”

VERVE-101 is delivered as a single IV infusions into the blood, and the lipid nanoparticles are taken out from the blood by hepatocytes in the liver through the LDL receptor. Bellinger explained further that a a single ATG spelling change made in the DNA sequence can permanently turn off the gene, turning off PCSK9 production as a result.

“Could there be editing happening at another spot other than the intended 1 in PCSK9? Reassuringly, in human liver cells treated with VERVE-101, there is no evidence for off-target editing,” said Bellinger during the session. “We looked across the entire genome and there was only the [single ATG spelling change] at the intended site on chromosome 1 in PCSK9.”

The heart-1 study is an open-label, single-ascending dose phase 1b study that enrolled a total of 10 individuals. Patients received a single, peripheral intravenous infusion of VERVE-101 and were evaluated across 4 dosing cohorts: 0.1 mg per kg (n = 3), 0.3 mg per kg (n = 3), 0.45 mg per kg (n=3), and 0.6 mg per kg (n = 1). Participants included males and females aged 18 to 75 years with HeFH, established severe ASCVD, and uncontrolled LDL-C who were on maximally tolerated oral lipid-lowering therapies. In addition, participants were at a high risk for cardiovascular events, both in the near-term and lifetime.

The primary endpoint of the study is the safety and tolerability of VERVE-101. Additional endpoints include pharmacokinetics of VERVE-101 as well as improved blood PCSK9 and LDL-C after 28 days.

“Recent FDA guidance for human genome editing suggested that a first-in-human trial of a gene editing medicine should include patients with severe advanced disease. Consistent with [that] guidance, the initial 10 participants in the study had severe advanced ASCVD and their risk for cardiovascular events was high, both over the near-term and lifetime,” explained Bellinger during the session.

After 28 days, the results indicated reductions of 47%, 59%, and 84% in blood PCSK9 protein levels in the and reductions of 39%, 48%, and 55% in blood LDL-C levels in the 2 higher dose cohorts (0.45 mg per kg and 0.6 mg per kg) following VERVE-101 administration.

Bellinger noted that the adverse events (AEs) were consistent with the severe advanced status of the enrolled patients. The most common AEs included reactions to the infusions, headache, and mild fever, which were reported to resolve quickly.

The serious adverse events (SAEs) observed in patients were consistent with complications in a severe, advanced ASCVD patient population. A total of 3 cardiovascular SAEs had occurred in 2 participants, of which 2 were determined to be unrelated to VERVE-101 treatment. A fatal cardiac arrest in the 0.3 mg per kg cohort had occurred approximately 5 weeks after infusion; however, the patient had ischemic cardiomyopathy at baseline and a previous history of cardiac arrest as well as severe underlying coronary artery disease. In the 0.45 mg per kg cohort, MI had occurred the day after infusion, and NSVT occurred over 4 weeks after infusion.

“VERVE-101 provides the first proof of concept for in vivo DNA base editing in humans [and it] led to dose-dependent productions in blood PSCK9 and LDL-C…The LDL changes have been durable to 6 months so far, consistent with [previous] data up to 2.5 years, and the safety profile supports continued development,” said Bellinger during the session.”

Next steps in the heart-1 trial will involve enrolling in 0.45 and 0.6 mg per kg cohorts to a complete dose escalation phase as well as expanded cohort sizes in future trials. Further, Bellinger noted that a randomized and placebo-controlled phase 2 trial for the PCSK9 program will occur in 2025.

“In patients who require deep LDL-C lowering over decades, VERVE-101 may emerge as a single-course treatment option to overcome limitations of the chronic care model,” said Bellinger during the session.


Bellinger, A. AHA Scientific Sessions 2023 Main Event. Presented at: AHA Scientific Sessions 2023; November 12, 2023.

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