VERVE-101: a promising CRISPR-based gene editing therapy that reduces LDL-C and PCSK9 levels in HeFH patients

Abstract

Low-density lipoprotein cholesterol (LDL-C) is a key risk factor for atherosclerotic cardiovascular disease (ASCVD). Despite significant advancements in lipid modification therapies, including statins, many patients with heterozygous familial hypercholesterolemia (HeFH) fail to reach the desired LDL-C target levels. PCSK9, a newly identified enzyme, binds to the LDL receptor and promotes its degradation. While antibodies or siRNA against PCSK9 can significantly reduce LDL-C and cardiovascular events,1,2 they require regular, long-term administration. Recent breakthroughs in CRISPR-based genome editing, specifically the CRISPR-Cas9 base editor, allow for the modification of single nucleotide bases without necessitating double-stranded DNA breaks.3,4 This technology reduces off-target effects and enhances accuracy, making it suitable for clinical applications. VERVE-101, a CRISPR-based gene editing therapy, uses messenger RNA for an adenine base editor and a guide RNA targeting the PCSK9 gene. Packaged in a lipid nanoparticle delivery vehicle, it is administered systemically as a one-time intravenous infusion. This A/T to G/C base pair editing disrupts the PCSK9 splice donor site, inactivating the PCSK9 gene in the liver. This method has proven effective in reducing PCSK9 and LDL-C levels in both nonhuman primates and mice, with the LDL-C lowering effect in nonhuman primates lasting for over a year.5 The heart-1 clinical trial (NCT05398029), a first-in-human phase 1b, open-label study, was designed to assess the safety and tolerability of VERVE-101. Its interim results were presented at the American Heart Association's Scientific Sessions 2023 in Philadelphia on 12 November, 2023. In the heart-1 clinical trial, VERVE-101 was administered as a singular peripheral intravenous infusion. Ten participants, comprising eight males and two females with an average age of 54 years, received VERVE-101 across four dose cohorts ranging from 0.1 to 0.6 mg/kg. These individuals exhibited HeFH, with a mean LDL-C of 193 mg/dL at screening. Nearly all participants had a history of coronary revascularization, including coronary artery bypass and percutaneous coronary intervention. Sub-therapeutic doses (0.1 mg/kg: n = 3, 0.3 mg/kg: n = 3) were administered to six participants, while four individuals received potentially therapeutic doses (0.45 mg/kg: n = 3, 0.6 mg/kg: n = 1). Nine participants reached a minimum of 28 days of follow-up and underwent analysis; one participant who received the 0.45 mg/kg dose had not reached day 28. Reductions of 39% and 48% in LDL-C were observed in the two participants receiving 0.45 mg/kg, and a 55% reduction was noted in one participant taking 0.6 mg/kg. PCSK9 levels decreased by 59% and 84% in the two participants taking 0.45 mg/kg and by 47% in one participant taking 0.6 mg/kg. The participant who received 0.6 mg/kg demonstrated a sustained 55% reduction in LDL-C levels up to 180 days. Transient infusion reactions and reversible increases in ALT, with mean bilirubin levels below the upper limit of normal, were observed. Three cardiovascular serious adverse events (SAEs) occurred in two participants. One participant (0.3 mg/kg) experienced a fatal cardiac arrest approximately 5 weeks after infusion, determined to be unrelated. The other (0.45 mg/kg) had a myocardial infarction the day after infusion, considered potentially related to the treatment due to proximity, and non-sustained ventricular tachycardia at more than 4 weeks after infusion, determined as unrelated. The independent data and safety monitoring board concurred that SAEs were consistent with a severe, ASCVD patient population. CRISPR-based in vivo gene editing holds substantial promise in the medical field; nevertheless, it is not without risks, including off-target effects, uncertain long-term consequences, and ethical considerations, although they are mitigated. Despite reservations regarding the long-term effects and safety of VERVE-101, the results of the inaugural clinical trials in humans are optimistic. This ground-breaking CRISPR-based gene editing therapy for PCSK9 presents a hopeful avenue for treating patients with HeFH, potentially mitigating the risk of ASCVD in the near future. No new data were generated or analysed in support of this research. Conflict of interest: None declared.

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