by A groundbreaking clinical trial has produced promising interim results by using CRISPR gene-editing technology to permanently reduce levels of low-density lipoprotein cholesterol (LDL-C), commonly known as “bad” cholesterol. The trial focused on individuals with a genetic condition called heterozygous familial hypercholesterolemia (HeFH), which leads to elevated levels of LDL-C and an increased risk of early heart attack.
LDL-C is a major contributor to atherosclerosis, the buildup of plaque on blood vessel walls that can result in heart attacks and stroke. While lifestyle changes and medication can help lower LDL-C, some individuals struggle with high cholesterol due to genetic factors, making it difficult to reach optimal levels.
The ongoing trial, the first in humans, utilized a single infusion of a gene-editing treatment called VERVE-101. Administered intravenously, this treatment uses CRISPR gene-editing technology to permanently silence the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene in the liver. The PCSK9 gene regulates LDL-C levels through its control of the LDL receptor, a protein responsible for removing cholesterol-rich LDL particles from the bloodstream.
Prior to the human trial, researchers tested VERVE-101 on animals and observed significant reductions in PCSK9 protein levels (67-83%) and LDL-C (49-69%) that lasted up to 476 days. The treatment also proved to be well-tolerated by the animals, with only a brief rise in liver enzymes that resolved within two weeks.
The current trial included nine participants diagnosed with HeFH and experiencing high LDL-C despite taking cholesterol-lowering medication. The participants, who had an average age of 54, had pre-existing severe coronary artery disease and a history of heart attacks, coronary bypass surgeries, or stent insertions.
Each participant received a single infusion of VERVE-101, with the doses escalating from 0.1 mg/kg to a maximum of 0.6 mg/kg. The results showed that individuals who received doses of 0.45 mg/kg and 0.6 mg/kg experienced LDL-C reductions of 39-55% and PCSK9 protein reductions of 47-84%. One participant who received the highest dose maintained reduced LDL-C levels at the six-month mark.
The study is still ongoing, but the researchers noted that most adverse events related to the trial were mild and unrelated to the treatment. Serious adverse cardiovascular events occurred in two participants with advanced coronary artery disease, including cardiac arrest, heart attack, and arrhythmias. However, the study’s independent data safety monitoring board deemed these safety events acceptable, and the trial will continue as planned.
While these interim results are promising, the study has its limitations. The participant pool is relatively small, and all participants received the treatment, making it challenging to compare the results directly with an alternate or no treatment. The study primarily measured LDL-C reductions rather than changes in heart attack occurrences. However, LDL-C reduction is a widely accepted and validated endpoint for patients with HeFH and coronary artery disease.
The trial is still enrolling participants for the higher doses of VERVE-101 and will continue to closely monitor their progress for the next 14 years, as required by the FDA for human genome editing trials.
In the current market, PCSK9 inhibitors, such as alirocumab and evolocumab, are approved for lowering LDL-C levels when other cholesterol-lowering drugs fail or are not well-tolerated. However, these drugs require regular injections and can be costly without insurance coverage. If VERVE-101 proves to be safe and effective, it could provide an alternative treatment option, requiring only a single dose that could provide long-lasting benefits for decades to come.
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1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it
