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New gene therapy can cut ‘bad’ cholesterol by 50% with a single dose

Millions of people taking statins daily to lower their cholesterol levels can benefit from a new gene therapy that has shown potential to reduce ‘bad’ cholesterol levels by up to 50 per cent with just one dose.

The single infusion of a CRISPR-based gene-editing therapy VERVE-101, developed by Verve Therapeutics in Boston, US, significantly reduced low-density lipoprotein cholesterol (LDL) also known as the “bad cholesterol” in people who carry one gene for the inherited condition that results in very high LDL cholesterol levels and a high risk of heart attack at an early age.

The investigational treatment uses DNA-editing technology to permanently turn off the PCSK9 gene in the liver.

PCSK9 is a gene that plays a critical role in controlling blood LDL-C through its regulation of the LDL receptor.

“Instead of daily pills or intermittent injections over decades to lower bad cholesterol, this study reveals the potential for a new treatment option — a single-course therapy that may lead to deep LDL-C lowering for decades,” said Andrew M. Bellinger, chief scientific officer at Verve Therapeutics.

The study presented at the American Heart Association’s Scientific Sessions 2023 in Philadelphia, described the first human trial of VERVE-101, which included 7 men and 2 women in New Zealand, and the UK.

Each participant was diagnosed with heterozygous familial hypercholesterolemia — meaning they inherited one gene for the disorder from one parent — and had extremely high bad cholesterol levels (average measure of 201 mg/dL) despite taking the maximum-tolerated LDL cholesterol- lowering medication.

The majority of study participants had pre-existing severe coronary artery disease and had already experienced a heart attack, or undergone coronary bypass surgery or stenting to allow adequate blood flow to heart muscle. None were taking PCSK9 inhibitors while enrolled in the study.

Each participant received a single intravenous infusion of VERVE-101, with the first cohort receiving a low dose of 0.1 mg/kg and other cohorts receiving escalating doses, after consultation with an independent safety monitoring board. The highest dose received was 0.6 mg/kg.

The study found that the highest-two VERVE-101 doses reduced LDL-C by 39 per cent and 48 per cent in the two participants receiving 0.45 mg/kg of the drug and 55 per cent in the sole participant receiving 0.6 mg/kg. It reduced blood PCSK9 protein levels by 47 per cent, 59 per cent and 84 per cent in the three participants receiving the 0.45 mg/kg or 0.6 mg/kg doses.

The drug also reduced LDL-C at six months in the sole participant receiving 0.6 mg/kg, with follow-up ongoing.

To date, most adverse events that occurred in the study were mild and unrelated to treatment. Serious adverse cardiovascular events, specifically a cardiac arrest, a myocardial infarction and an arrhythmia, occurred in two patients who had underlying advanced coronary artery disease, the study showed.

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