Abstract Body (Do not enter title and authors here): Introduction: Maintaining LDL-C at goal levels is critical in populations at high risk for cardiovascular events, including people with heterozygous familial hypercholesterolemia (HeFH) and/or premature coronary artery disease (CAD). Despite multiple approved LDL-C lowering therapies for these populations, most patients are not at guideline-directed treatment goal. In vivo base editing to inactivate hepatic PCSK9 has the potential to provide lifelong LDL-C lowering after a single course of treatment. Success of the base editing approach is contingent on safe and effective hepatocyte delivery and precise, consistent PCSK9 editing.
Aim: We set out to develop a base editing medicine to inactivate PCSK9 with broad utility across diverse genetic backgrounds. Here we describe the investigational therapy, VERVE-102, and the design of the ongoing, phase 1b Heart-2 trial.
Approach: VERVE-102 consists of an mRNA encoding an adenine base editor and guide RNA (gRNA) targeting PCSK9 packaged in a novel, proprietary GalNAc lipid nanoparticle (LNP). VERVE-102 creates a precise A-to-G DNA edit to introduce a premature stop codon and thereby inactivate PCSK9 in hepatocytes. In a DNA sequence analysis of 784,318 individuals from diverse ancestries, the 20 base-pair sequence targeted by the gRNA was identical in 99.97% of individuals. LNP delivery to hepatocytes in vivo occurs through either endogenous LDL receptor (LDLR) uptake or GalNAc-mediated endocytosis via the asialoglycoprotein receptor (ASGPR) and as such, may address the LDLR deficiency seen in a fraction of patients with HeFH. Heart-2 is a single ascending dose trial of VERVE-102 in males and females aged 18–65 with HeFH and/or premature CAD who require additional LDL-C lowering despite maximally tolerated oral lipid-lowering therapies. Participants receive a single intravenous infusion of VERVE-102 with 3 to 9 participants per dose cohort. The primary endpoint is safety and tolerability. Secondary endpoints include pharmacokinetics of VERVE-102 and changes from baseline in blood PCSK9 and LDL-C.
Discussion: VERVE-102 was designed to access hepatocytes via either LDLR- or ASGPR-mediated uptake to enable robust LNP delivery and subsequent PCSK9 editing. Consistency of the gRNA target site suggests that potential therapeutic benefits should apply broadly across ancestries. The ongoing Heart-2 clinical trial is intended to support selection of a safe and effective dose for future clinical investigation of VERVE-102.