Research Highlights:
Embargoed until 3:30 p.m. ET, Sunday, Nov. 12, 2023
PHILADELPHIA, Nov. 12, 2023 — A single infusion of a CRISPR-based gene-editing therapy significantly reduced low-density lipoprotein cholesterol (LDL, 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, according to late-breaking science presented today at the American Heart Association’s Scientific Sessions 2023 . The meeting, Nov. 11-13, in Philadelphia, is a premier global exchange of the latest scientific advancements, research and evidence-based clinical practice updates in cardiovascular science.
“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 senior study author Andrew M. Bellinger, M.D., Ph.D., chief scientific officer at Verve Therapeutics in Boston.
The investigational treatment, VERVE-101, 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. The study presented today is the first human trial of VERVE-101.
Earlier this year, the results of the researchers’ one-year animal study were published in Circulation . In that animal study, VERVE-101 lowered PSCK9 levels 67%-83% and bad cholesterol 49%-69%, depending on the dose. After a single dose, the reductions have now lasted 2.5 years, supporting the idea that VERVE-101 may potentially be an effective long-term or permanent treatment for high LDL-C.
The ongoing, first-in-human study included 7 men and 2 women in New Zealand or the United Kingdom: average age of 54 years; 8 white adults; and 1 Asian adult. 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.
“These numbers are consistent with the fact that, despite available treatments, only about 3% of patients living with heterozygous familial hypercholesterolemia globally have reached target treatment goals,” Bellinger said.
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 (n=3) 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:
“We were thrilled to see that the previous testing we had done of VERVE-101 in animal models translated faithfully to these findings in humans,” Bellinger said.
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. “All safety events were reviewed with the independent data safety monitoring board, who recommended continuation of trial enrollment with no protocol changes required,” Bellinger said.
Background:
Among the study’s limitations is that this is an interim report with a few participants who all received the treatment; therefore, no participants receiving an alternate treatment or no treatment were available for direct comparison. Results in the study were measured by reductions in LDL-C, not changes in the occurrence of heart attacks; however, LDL-C reduction is a well-known, validated endpoint among patients with heterozygous familial hypercholesterolemia and coronary artery disease.
It is estimated that one in about 200 adults have the familial hypercholesterolemia genetic mutation, affecting about 1.3 million adults and children in the U.S. High bad cholesterol contributes to atherosclerotic plaques , leading to a much higher-than-normal risk of heart disease . If left untreated, people with the disorder have 20 times the risk of developing heart disease, according to the American Heart Association . The other type of familial hypercholesterolemia, called homozygous familial hypercholesterolemia, is when someone inherits the gene for the disorder from both parents, and it is rare and more severe.
Co-authors and disclosures are listed in the abstract. The study is funded by Verve Therapeutics.
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