Our Therapeutic Vision
We are taking a stepwise approach to clinical development with our single-course gene editing programs, focused initially on addressing disease populations that have genetically driven, life-long and severely elevated LDL-C, such as familial hypercholesterolemia (FH). As we establish safety and efficacy, we plan to expand our focus to address progressively larger populations of patients with or at risk for ASCVD.
STEP 1: Our initial focus will be on adults with FH, a genetic disease caused by life-long severely elevated LDL-C that leads to increased risk of early-onset ASCVD, and affecting approximately 1.3 million in the U.S. and 31 million globally.
STEP 2: We will expand to patients with established ASCVD, who have a high risk for future events.
STEP 3: We plan to further expand to all adults at risk for ASCVD in the general population.
We are advancing a pipeline of single-course in vivo gene editing programs intended to safely and durably turn off genes in the liver implicated in CVD. Our initial programs target PCSK9 and ANGPTL3, two genes that have been extensively validated via human genetics and human pharmacology as targets for lowering blood lipids. We envision expanding beyond our PCSK9 and ANGPTL3 programs to develop a suite of single-course gene editing medicines that could comprehensively and robustly address additional independent causes of ASCVD in the future.
VERVE-101: Heterozygous Familial Hypercholesterolemia (HeFH)
Our lead product candidate, VERVE-101, is designed to be a single-course in vivo liver gene editing treatment. We plan to develop VERVE-101 initially for patients with HeFH. Individuals with FH may harbor one mutant allele and are thereby heterozygous for the disease.
In patients with HeFH, a genetic mutation in the LDLR gene down-regulates LDLR expression, which leads to extremely high LDL-C levels in the blood. Over time, high LDL-C builds up in the arteries, resulting in reduced blood flow or blockage, and ultimately heart attack or stroke. Inactivation of the PCSK9 gene can increase LDLR expression, resulting in lower LDL-C levels and reduced risk for heart attack and ASCVD.
Editing the PCSK9 Gene
VERVE-101 utilizes LNP-mediated delivery to target the liver and base editing technology to make a single A-to-G base change at a specific site in the PCSK9 gene in order to disrupt PCSK9 protein production, which subsequently lowers LDL-C levels in the blood.
Our gene editing medicine is comprised of a messenger RNA (mRNA) and a guide RNA (gRNA) packaged in a lipid nanoparticle (LNP); the medicine precisely edits and permanently turns off a target gene in the liver using base editing to make a single spelling change in DNA. Learn more about the mechanism of action for our lead product candidate, VERVE-101, which uses adenine base editing to knock out the PCSK9 gene to permanently lower blood levels of LDL cholesterol (LDL-C) and treat cardiovascular disease (CVD):
Encouraging Preclinical Results
In an in vivo proof-of-concept study, a single intravenous infusion of a base editor targeting PCSK9 achieved 67% whole liver DNA editing and resulted in an 89% reduction in blood levels of PCSK9 protein and a 59% reduction in blood levels of LDL-C in non-human primates (NHP) at two weeks as compared to baseline.
Both the PCSK9 protein and LDL-C reductions were durably maintained out to six months following treatment.
VERVE-101 has been generally well tolerated following a single administration in preclinical studies in NHPs, with only mild elevations in liver function tests that resolved within two weeks. In primary human hepatocytes treated with VERVE-101, on-target editing at the PCSK9 target site was observed, with no evidence of editing at any of 141 identified potential off-target sites.
Our second gene editing program is designed to target the ANGPTL3 gene, a regulator of cholesterol and triglyceride metabolism. The ANGPTL3 gene has recently emerged as a new and promising target for severe hyperlipidemia. We plan to develop our ANGPTL3 program initially for patients with FH, including patients with either HoFH, who have two mutant alleles, or those with HeFH. In a similar fashion to VERVE-101, we believe that our ANGPTL3 program will be applicable beyond FH to all patients with or at risk for ASCVD, and we plan to follow a similar stepwise approach to development.