We are developing two product candidates targeting PCSK9 – VERVE-101 and VERVE-102. These single-course treatments are designed to permanently inactivate the PCSK9 gene in the liver to reduce disease-driving LDL-C.
VERVE-101
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, as presented at AHA, here, as well as results from the updated durability dataset, as presented at the European Society of Cell and Gene Therapy 31st Annual Congress in October 2024, here.
13 participants have been 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]). Mean, time-averaged PCSK9 protein reductions of greater than 60% were observed in each of the two higher dose cohorts, 0.45 mg/kg and 0.6 mg/kg. Mean, time-averaged LDL-C reductions of 42% at 0.45 mg/kg (n=6) and time-averaged LDL-C reduction of 57% at 0.6 mg/kg (n=1) were observed. The mean reductions in LDL-C and PCSK9 protein were based on time-averaged reductions from day 28 through last available follow up, as of a data cut-off date of October 3, 2024. In the single participant at the highest dose cohort, LDL-C reduction has now been sustained out to 18 months after a single dose, 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. Based on additional nonclinical studies conducted as part of its investigation into the laboratory abnormalities, Verve continues to believe that the LNP in VERVE-101 is likely the primary driver of the abnormalities. The VERVE-101 Investigational New Drug Application (IND) in the U.S. and Clinical Trial Applications (CTAs) in the U.K. and New Zealand are active, though the trial remains paused as Verve focuses its efforts on VERVE-102.
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).
VERVE-102 is currently being evaluated in our Heart-2 Phase 1b clinical trial in patients with HeFH or premature coronary artery disease.
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.