Verve Therapeutics Announces Interim Data for VERVE-101 Demonstrating First Human Proof-of-Concept for In Vivo Base Editing with Dose-Dependent Reductions in LDL-C and Blood PCSK9 Protein in Patients with Heterozygous Familial Hypercholesterolemia - Seite 2

heart-1 Clinical Trial Design
heart-1 is an open-label, phase 1b clinical trial in patients living with HeFH, established ASCVD and uncontrolled hypercholesterolemia. The trial is designed to evaluate the safety and tolerability of VERVE-101, with additional analyses for pharmacokinetics and pharmacodynamic reductions in blood PCSK9 protein and LDL-C. Single doses of 0.1 mg/kg (n=3), 0.3 mg/kg (n=3), 0.45 mg/kg (n=3), and 0.6 mg/kg (n=1) of VERVE-101 have been administered via intravenous infusion. Initial safety data reported are from all ten patients enrolled as of a data cut-off date of October 16, 2023. One patient who received a 0.45 mg/kg dose had not reached day 28 as of the data cut-off date and is not included in the efficacy analysis.

Patients included in both the safety and efficacy analyses have had a high burden of coronary artery disease, consistent with the 2022 U.S. Food and Drug Administration (FDA) draft guidance for human genome editing products¹ that suggests a first-in-human trial include patients with severe, advanced disease. Nine patients have had prior coronary revascularizations with either coronary artery bypass grafting or coronary stenting procedures and four have had prior myocardial infarctions. With a mean screening LDL-C of 193 mg/dL, none of the patients were at LDL-C goal on maximally tolerated oral lipid-lowering therapy.

heart-1 Efficacy Analysis
Following a single infusion of VERVE-101, dose-dependent reductions in pharmacodynamic measures of blood PCSK9 protein levels were observed, suggesting successful editing at the intended genomic target. Dose-dependent LDL-C reductions, a validated measure of clinical efficacy for this patient population, were observed one month after treatment.

In the interim dataset, six patients were treated at sub-therapeutic doses (0.1 mg/kg and 0.3 mg/kg) and three patients were treated at potentially therapeutic doses (0.45 mg/kg and 0.6 mg/kg). The two patients treated with 0.45 mg/kg of VERVE-101 had a time-averaged blood PCSK9 protein reduction of 59% and 84%. The patient treated with 0.6 mg/kg of VERVE-101 had a time-averaged blood PCSK9 protein reduction of 47%.

The two patients treated with 0.45 mg/kg of VERVE-101 had a time-averaged LDL-C reduction of 39% and 48%. The patient treated with 0.6 mg/kg of VERVE-101 had a time-averaged LDL-C reduction of 55%. In this single participant in the highest dose cohort, the 55% reduction in LDL-C was durable out to 180 days, with follow-up ongoing.