Verve is taking a stepwise approach to clinical development that first takes aim at adults with life-threatening coronary heart disease and high unmet medical need. As we establish safety and efficacy, we will widen our clinical focus to include progressively larger populations with or at risk for disease.
Our Therapeutic Vision
Explore Verve’s clinical development plan:
STEP 1: Verve’s initial focus will be on adults with familial hypercholesterolemia (FH), a genetic disease that causes early coronary heart disease and death. Approximately 1 million people have FH in the United States.
STEP 2: Verve will then expand to those with established atherosclerotic cardiovascular disease and a high risk for future events.
STEP 3: Verve will then offer its gene editing medicines to all adults at risk for coronary heart disease in the general population.
We are building a pipeline of gene editing medicines that safely turn off a gene in the liver and durably lower blood levels of LDL cholesterol, triglycerides, or lipoprotein(a) to treat coronary heart disease. We are pursuing highly validated gene targets, identified by human genetics, that have been shown to confer near-complete protection from coronary heart disease. These genes impact lipoprotein pathways which play a critical role in transporting lipids throughout the body. Each pathway affects heart attack risk in different ways. Verve is developing product candidates to target each of these pathways.
VERVE-101: Heterozygous Familial Hypercholesterolemia
Our lead product candidate, VERVE-101, is a gene editing medicine in development for the treatment of heterozygous familial hypercholesterolemia, a genetic disease that causes high LDL cholesterol levels and leads to early coronary heart disease and heart attack. The disease affects approximately 1 in 200 to 500 individuals worldwide.1 Many people with HeFH do not reach target LDL cholesterol levels with currently available treatment approaches.2
Individuals with HeFH have a genetic mutation, typically in the LDL receptor (LDLR) gene, which down-regulates LDLR expression, causing extremely high LDL cholesterol levels in the blood. Inactivation of the PCSK9 gene has been shown to up-regulate LDLR expression and lower LDL cholesterol levels, reducing the risk for coronary heart disease.3
Editing the PCSK9 Gene
VERVE-101 is designed to be a one-time treatment that turns off the PCSK9 gene using base editing. Base editing—which Verve has exclusively licensed from Beam Therapeutics for certain cardiovascular targets—is a gene editing technology which enables the precise and permanent rewriting of a single DNA letter in the genome. By making a single A-to-G change in the genetic sequence of PCSK9, VERVE-101 permanently inactivates the gene.
Encouraging Preclinical Results
VERVE-101 consists of an adenine base editor messenger RNA and an optimized guide RNA packaged in a lipid nanoparticle delivery system. It is administered in-vivo through a single intravenous infusion. In non-human primate studies, VERVE-101 was shown to safely and precisely knock out PCSK9 in the liver, resulting in a substantial reduction in blood levels of PCSK9 protein and blood levels of LDL cholesterol.
Specifically, a single injection of VERVE-101 achieved 67% whole liver DNA editing and resulted in a 89% reduction in blood levels of PCSK9 protein and a 59% reduction in blood levels of LDL cholesterol in primate models at two weeks as compared to baseline. Additionally, in studies of VERVE-101 in primary human hepatocytes, there was clear evidence of on-target editing with no evidence of off target editing. VERVE-101 is currently being evaluated in IND-enabling studies.
- Nordestgaard BG et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013;34(45):3478-90a (Link)
- Mach F et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111-188 (Link)