VERVE-101, a single-course in vivo liver base editing medicine, is currently being evaluated in our Phase 1b heart-1 clinical trial in patients with high-risk heterozygous familial hypercholesterolemia (HeFH), established atherosclerotic cardiovascular disease (ASCVD), and uncontrolled LDL-C levels on oral standard-of-care therapy.
HeFH is characterized by extremely high LDL-C levels in the blood that, over time, cause plaque to build up in the arteries, resulting in reduced blood flow or blockage. This significantly increases an individual’s risk for heart attack and stroke. Inactivation of the PCSK9 gene in the liver can be effective in lowering LDL-C levels.
We believe that VERVE-101 has the potential to treat a broad population of patients and plan to take a stepwise approach for its clinical development. If our Phase 1b heart-1 clinical trial to evaluate the safety and efficacy of VERVE-101 in patients with high-risk HeFH is successful, we plan to expand into the broader HeFH population, and then ultimately target larger patient groups with established ASCVD.
Encouraging Preclinical Results
In an ongoing long-term study in 36 non-human primates (NHP), we administered 1.5 mg/kg of VERVE-101 (n=22) and 0.75 mg/kg (n=4), with a control group (n=10). The study was designed to measure whole liver editing, blood PCSK9 protein levels and blood LDL-C levels.
At the 1.5 mg/kg dose level, we observed an average of 70% whole liver editing at the PCSK9 target site at day 15, which we believe represents editing of the majority of hepatocytes. We also observed a PCSK9 protein reduction of approximately 79% and a robust LDL-C reduction of approximately 62% at two weeks following treatment, which improved to 89% and 68%, respectively, at one year following treatment. At the 0.75 mg/kg dose level, we observed a PCSK9 protein reduction of approximately 54% and a robust LDL-C reduction of approximately 38% at two weeks following treatment, which improved to 69% and 50%, respectively, at one year following treatment.
VERVE-101 was generally well tolerated in NHP studies, with only mild elevations in liver function tests that resolved within two weeks. These findings are consistent with observations from nonclinical studies performed for an approved LNP-based product that is administered intravenously.
