Verve Therapeutics, Inc. highlighted key milestones anticipated in 2022 and announced new preclinical data in non-human primates (NHPs) on additional potential dosing regimens for its base editing programs for the treatment of atherosclerotic cardiovascular disease (ASCVD) indications. Verve's lead program, VERVE-101, is designed to permanently turn off the PCSK9 gene in the liver to reduce disease-driving LDL-C. VERVE-101 is being developed initially for the treatment of patients with heterozygous familial hypercholesterolemia (HeFH), a potentially fatal genetic heart disease. Previously reported data in NHPs demonstrated that a single administration of VERVE-101 led to robust, durable editing of the PCSK9 gene.

Key program milestones anticipated in 2022 include: Clinical trial application (CTA) and investigational new drug (IND) submissions in the second half of 2022, and First HeFH patient treated in a Phase 1 clinical trial in the second half of 2022. Verve's second program is designed to permanently turn off the ANGPTL3 gene, a key regulator of cholesterol and triglyceride metabolism. Verve plans to develop this program initially for the treatment of both homozygous familial hypercholesterolemia (HoFH) and HeFH.

Previously reported data have demonstrated that a single administration of Verve's ANGPTL3-targeting base editor led to potent reductions in blood ANGPTL3 protein levels and LDL-C in a novel NHP model of HoFH. Key program milestones anticipated in 2022 include: Development candidate selection in the second half of 2022, and IND-enabling studies to begin in the second half of 2022. Given the complexities of ASCVD indications, some patients may benefit from additional lipid lowering after treatment with any single agent.

Verve conducted multiple preclinical assessments in NHPs to explore the potential to re-dose or sequentially dose its gene editing treatments. To assess the potential for repeat dosing, Verve conducted a study in NHPs (n=4), in which 0.5 mg/kg of a VERVE-101 precursor was dosed on days 1, 30 and 60 in a 90-day study. Editing of PCSK9 was measured in liver biopsy after each dose on days 14, 46 and 75, and in liver necropsy on day 90.

Verve observed an increase in PCSK9 editing over the course of the study, with an average of 29% at day 14, 36% at day 46, 53% at day 75 and 59% at day 90. These data suggest that repeat low doses of a PCSK9 base editor could achieve a high level of liver editing. Importantly, no evidence of liver injury was observed following any of the doses, which provides evidence of the low immunogenicity of LNPs in NHPs.

Patients with very high LDL-C or those with combined hyperlipidemia with high LDL-C and high triglycerides may benefit from gene editing medicines that target two lipid pathways, such as PCSK9 and ANGPTL3. To assess the potential for sequential dosing, Verve conducted a 90-day study in NHPs (n=4), in which 1.0 mg/kg of a VERVE-101 precursor was administered on day 1, followed by administration of 1.0 mg/kg of an ANGPTL3 base editor on day 30. PCSK9 editing was measured by liver biopsy on day 15, showing an average of 71% editing, and ANGPTL3 editing was measured in a second liver biopsy on day 45, showing an average of 52% editing.

In liver necropsy on day 90, an average of 69% PCSK9 editing and 63% ANGPTL3 editing was observed. Verve monitored plasma PCSK9 and ANGPTL3 protein levels during the study and observed a greater than 90% reduction of plasma PCSK9 protein after the first dose and a greater than 90% reduction of plasma ANGPTL3 protein after the second dose, with both reductions remaining durable to the conclusion of the study. These data suggest that sequential dosing of a PCSK9 base editor followed by an ANGPTL3 base editor may be administered to efficiently edit two genes that control key lipid pathways.