Verve Therapeutics announced updates from the Heart-1 Phase 1b clinical trial of VERVE-101 and clearance of its Clinical Trial Applications by the U.K. Medicines and Healthcare products Regulatory Agency and Health Canada for VERVE-102, with the Heart-2 Phase 1b clinical trial expected to initiate in the second quarter of this year. VERVE-101 is being evaluated in the Heart-1 Phase 1b clinical trial with trial endpoints of safety and tolerability as well as changes in blood PCSK9 protein and low-density lipoprotein cholesterol (LDL-C) levels in patients living with heterozygous familial hypercholesterolemia, established atherosclerotic cardiovascular disease (ASCVD), and uncontrolled hypercholesterolemia. Six participants have been dosed at 0.45 mg/kg of VERVE-101, with a total of 13 participants dosed in the study.

For the first five participants in the 0.45 mg/kg cohort with follow-up to at least 28 days, VERVE-101 demonstrated time-averaged LDL-C reductions ranging from 21% to 73%, and averaging 46% (as of a data cut-off date of March 18, 2024). In the two patients with the longest follow-up in the 0.45 mg/kg or 0.6 mg/kg cohorts, LDL-C lowering has been durable out to 270 days, with follow-up ongoing. However, the sixth participant treated in the 0.45 mg/kg cohort experienced a Grade 3 drug-induced transient increase in serum alanine aminotransferase as well as a serious adverse event of Grade 3 drug-induced thrombocytopenia within the first four days after dosing.

The participant did not experience any bleeding or other symptoms related to the laboratory abnormalities, and the abnormalities resolved fully within a few days. In light of such observed laboratory abnormalities associated with VERVE-101, Verve, in consultation with the study?s independent data and safety monitoring board (DSMB), has decided to pause enrollment in the Heart-1 clinical trial. Verve is conducting an investigation into the laboratory abnormalities and based on those results, expects to work with regulatory authorities to define a path forward for VERVE-101.

These safety events were reported to the U.S. Food and Drug Administration (FDA), MHRA, and the New Zealand Medicines and Medical Devices Safety Authority (Medsafe). The VERVE-101 Investigational New Drug Application and other CTAs remain active. Verve is now prioritizing the development of VERVE-102 and the initiation of the Heart-2 clinical trial.

VERVE-102 uses the same base editor and guide RNA for PCSK9 but a different lipid nanoparticle delivery system than VERVE-101. VERVE-102 has two principal differences from VERVE-101. First, VERVE-102 includes a different ionizable lipid from VERVE-101.

VERVE-102?s ionizable lipid has already been used in third-party clinical trials of gene editing product candidates and has been well-tolerated in these trials. Second, the incorporation of GalNAc allows the LNP in VERVE-102 to access liver cells using either the asialoglycoprotein receptor (ASGPR) or the low-density lipoprotein receptor. Verve has received regulatory clearances for the Heart-2 clinical trial in the U.K. and Canada and plans to initiate the Heart-2 clinical trial in patients with HeFH or premature coronary artery disease in the second quarter of 2024.

VERVE-101 is a novel, investigational gene editing medicine designed to be a single course treatment that permanently turns off the PCSK9 gene in the liver to reduce disease-driving low-density lipoprotein cholesterol (LDL-C). VERVE-101 is being developed initially as a treatment for patients with heterozygous familial hypercholesterolemia (HeFH), a prevalent and potentially life-threatening subtype of atherosclerotic cardiovascular disease (ASCVD). VERVE-101 consists of messenger RNA expressing an adenine base editor and an optimized guide RNA targeting the PCSK9 gene packaged in an engineered lipid nanoparticle.

VERVE-102 is a novel, investigational gene editing medicine designed to be a single course treatment that permanently turns off the PCSK9 gene in the liver to reduce disease-driving low-density lipoprotein cholesterol (LDL-C), similar to VERVE-101. VERVE-102 is being developed initially as a treatment for patients with heterozygous familial hypercholesterolemia (HeFH) or premature coronary artery disease (CAD). VERVE-102 consists of messenger RNA expressing an adenine base editor and an optimized guide RNA targeting the PCSK9 gene, identical to VERVE-101.

However, VERVE-102 uses a different delivery system than VERVE-101, which includes a different ionizable lipid and Verve?s proprietary GalNAc liver-targeting ligand.