Our PCSK9 Programs

VERVE-101, a single-course in vivo liver base editing medicine, is currently being evaluated in our Heart-1 Phase 1b 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. 

VERVE-101: Heart-1 clinical data supports proof-of-concept for in vivo base editing of the PCSK9 gene in the liver 

The Heart-1 trial is designed to evaluate the safety and tolerability of VERVE-101, along with analyses of pharmacokinetics and changes in blood PCSK9 protein and LDL-C. 

In November 2023, we presented an interim dataset at the American Heart Association (AHA) Scientific Sessions 2023. Initial results from the Heart-1 trial indicated that treatment with VERVE-101 led to dose-dependent reductions of disease-causing LDL-C in people living with HeFH, and the safety profile was consistent with the severe, advanced ASCVD patient population enrolled. 

See full results from the interim dataset here. 

In April 2024, we announced that three additional patients have been dosed in the 0.45 mg/kg cohort, with a total of 13 patients dosed in the trial (0.1 mg/kg [n=3], 0.3 mg/kg [n=3], 0.45 mg/kg [n=6], and 0.6 mg/kg [n=1]). 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, due to observed laboratory abnormalities associated with VERVE-101, Verve has decided to pause enrollment in the Heart-1 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. The VERVE-101 Investigational New Drug Application (IND) in the U.S. and Clinical Trial Applications (CTAs) in the U.K. and New Zealand remain active.

We are committed to solving FH by targeting PCSK9, and we are currently evaluating a second PCSK9 gene editor, VERVE-102, further increasing our odds of addressing the unmet needs of patients with FH, and ultimately, those with or at-risk of ASCVD.

VERVE-102 is a single-course in vivo liver base editing medicine that aims to inactivate PCSK9 like VERVE-101. VERVE-102 uses the same base editor and guide RNA for PCSK9 but a different lipid nanoparticle (LNP) 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 (LDLR).  

We plan to initiate the Heart-2 Phase 1b trial of VERVE-102 in patients with HeFH or premature coronary artery disease in the second quarter of 2024.

We believe our PCSK9 product candidates have the potential to treat a broad population of patients and plan to take a stepwise approach for clinical development, starting with the HeFH population before larger patient groups with established ASCVD. Following an evaluation of clinical data from the Heart-1 and the Heart-2 trials, we plan to initiate a randomized, placebo-controlled Phase 2 clinical trial of either VERVE-101 or VERVE-102.