One-off gene-editing treatment lowers inherited bad cholesterol levels
Researchers have presented the interim results of a clinical trial that used a single infusion of CRISPR gene-editing technology to permanently switch off low-density lipoprotein cholesterol production in people with a genetic condition that causes elevated levels of the ‘bad’ cholesterol and increases the risk of early heart attack.
Low-density lipoprotein cholesterol (LDL-C), so-called ‘bad’ cholesterol, is known to be a primary driver of atherosclerosis, the build-up of plaque on the walls of blood vessels that places people at risk of heart attack and stroke. While lifestyle changes and medications are used to lower LDL-C, for some people, high cholesterol is a result of genetics, which makes reaching optimal LDL-C levels difficult.
In heterozygous familial hypercholesterolemia (HeFH), people inherit one gene that results in very high LDL-C levels and elevates the risk of heart attack at an early age. But interim results from an ongoing trial, the first in humans, have shown that a single infusion of a gene-editing treatment could significantly reduce LDL-C in people with HeFH, an effect that might be sustained for many years.
“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 Bellinger, chief scientific officer at Verve Therapeutics in Boston.
The investigative treatment, called VERVE-101, is delivered as a one-off intravenous infusion and uses CRISPR gene-editing technology to permanently turn off the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene in the liver, a gene that plays a critical role in controlling blood levels of LDL-C through its regulation of the LDL receptor, a protein that removes cholesterol-rich LDL particles from the plasma.
The researchers previously tested the efficacy and tolerability of VERVE-101 in animals, publishing their results in Circulation. In that study, the treatment lowered PSCK9 protein levels by 67% to 83% and LDL-C by 49% to 69%, depending on the dose administered, with effects lasting up to 476 days. After a transient rise in liver enzymes that was fully resolved by day 14, VERVE-101 was found to be well-tolerated by the animals.
The current trial included seven men and two women in New Zealand or the UK diagnosed with HeFH and having extremely high LDL-C despite taking cholesterol-lowering medication. The average age of participants was 54, and the majority had pre-existing severe coronary artery disease and had already experienced a heart attack, undergone coronary bypass surgery or had stents inserted.
“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.
Each participant received a single intravenous infusion of VERVE-101, with the first cohort of three receiving a low dose of 0.1 mg/kg. Other cohorts were given escalating doses, with the highest being 0.6 mg/kg, which only one participant received.
In the two participants who received a dose of 0.45 mg/kg, LDL-C was reduced by 39% and 48%. It was reduced by 55% in the sole participant who received 0.6 mg/kg. PCSK9 protein levels were reduced by 47%, 59% and 84% in the three participants receiving 0.45 mg/kg or 0.6 mg/kg. The participant who received a dose of 0.6 mg/kg had reduced LDL-C at six months.
“We were thrilled to see that the previous testing we had done of VERVE-101 in animal models translated faithfully to these finds in humans,” said Bellinger.
While the study is ongoing, the researchers say that most adverse events experienced by the participants have been mild and unrelated to treatment. Two participants with underlying advanced coronary artery disease had serious adverse cardiovascular events, specifically cardiac arrest, a heart attack, and an arrhythmia.
“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.
Among the study’s limitations is that this is an interim report with a small group of participants who all received the treatment. Therefore, no participants received an alternate treatment or no treatment 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 HeFH and coronary artery disease.
The study is still enrolling participants to receive the highest two doses of VERVE-101 – 0.45 mg/kg and 0.6 mg/kg. After a year, each participant will go into a long-term follow-up study for an additional 14 years, an FDA requirement for participants in any human genome editing trials.
In 2015, the US FDA approved two other PCSK9 inhibitors, alirocumab and evolocumab, as once-every-two-week injections for lowering LDL-C when statins and other drugs weren’t working or were poorly tolerated. But, in addition to requiring regular injections, these drugs are expensive and may not be covered by insurance. So, if VERVE-101 is deemed safe and effective, it could provide an alternative to existing treatments, requiring a single dose that, according to the researchers, could provide decades worth of benefits.
The researchers presented the interim report from their Phase 1b clinical trial at the American Heart Association’s Scientific Sessions 2023.
Source: American Heart Association