Conference Coverage

Promising first results with DNA editing to lower LDL


AT AHA 2023

PHILADELPHIA – The first in-human study of a gene therapy designed to reduce low-density lipoprotein cholesterol has shown a signal that the treatment works in a small group of patients with heterozygous familial hypercholesterolemia (HeFH).

While one of four patients in the highest-dose groups had a myocardial infarction the day after getting the treatment, investigators have enough confidence to go forward with the next phase of study.

“The HEART-1trial demonstrated the first human proof of concept for in vivo DNA-based editing,” said Andrew Bellinger, MD, PhD, chief scientific officer of Verve Therapeutics, the company developing the treatment. “We saw dose-dependent–based reductions in LDL and the PCSK9 protein.”

The HEART-1 study was a phase 1b trial of VERVE-101, a CRISPR-based gene editing mechanism designed to inactivate the liver gene PCSK9, which contributes to raising cholesterol. “Human genetics suggest that turning off the cholesterol-raising gene PCSK9 in the liver will durably reduce LDL cholesterol,” Dr. Bellinger said in presenting the results at the annual scientific sessions of the American Heart Association.

Lipid nanoparticle

VERVE-101 is designed to be a single-course treatment to specifically treat HeFH, Dr. Bellinger said. He explained how the therapy, given by intravenous infusion, differs from adeno-associated virus vectors that have dominated gene therapy platforms.

“It’s a lipid nanoparticle encapsulating two RNA nanoparticles that are taken up by hepatocytes in the liver from the blood by the LDL receptor,” he explained. “Then the A-to-G–based editor protein and the guide mRNA protein together find the PCSK9 gene in the liver.” That single DNA-base change in one position of the PCSK9 gene is able to turn off PCSK9 production in those liver cells.

Dr. Bellinger presented interim results of the first 10 patients treated in the open-label, single ascending dose study. The patients were male and female, ages 18-75, with HeFH, established atherosclerotic cardiovascular disease and uncontrolled hypercholesterolemia despite being on maximally tolerated lipid-lowering therapy.

They received four different doses: Three patients each received 0.1, 0.3, and 0.45 mg/kg; and one patient received 0.6 mg/kg.

Reductions in blood PCSK9 levels were measured across all dosing groups at 4 weeks, but they were most pronounced in the two highest groups, Dr. Bellinger said. Two patients in the 0.45-mg/kg group had reductions of 59% and 84%. The sole patient in the 0.6-mg/kg arm had a reduction of 47%.

Regarding the 84% reduction in one individual, Dr. Bellinger said, “Roughly 85% of PCSK9 comes from the liver. These data suggest that we have successfully made a single base pair change in both copies of the PCSK9 gene in nearly every hepatocyte in the liver of this individual.”

Those benefits carried over to LDL cholesterol measures, with the highest-dose patients registering 39%, 48% and 55% reductions.

Safety outcomes

Two patients had serious cardiovascular (CV) events. One in the 0.3-mg/kg arm died from cardiac arrest 5 weeks after receiving the infusion. A patient in the 0.45-mg/kg arm had a myocardial infarction a day after getting the infusion and then nonsustained ventricular tachycardia (NSVT) 4 weeks later. Dr. Bellinger said an independent review panel determined that the CV events were in line with outcomes for high-risk patients and weren’t directly related to treatment.

He added, “Increased liver transaminases were seen in patients treated in the higher-dose cohorts. It’s transient, asymptomatic, and it resolved quickly.”

The next step involves pursuing only the 0.45- and 0.6-mg/kg doses in the next dose-escalation phase and enrolling an expansion cohort in 2024, Dr. Bellinger said, with a plan to initiate a randomized, placebo-controlled phase 2 trial in 2025.

First, do no harm

Karol Watson, MD, PhD, a women’s cardiovascular disease specialist at UCLA, said the promise of gene therapy was “revolutionary,” but that proving safety was critical going forward.

“You’re changing the genome forever,” she said. “Safety is going to be of the utmost importance especially because there are currently safe and efficacious strategies available for lipid lowering. This is a strategy that could be revolutionary, but we have to make sure that it’s safe.”

She pointed to a multinational study from earlier this year that warned about pathogenic consequences from CRISPR-based gene editing. “There are concerns about gene editing,” Dr. Watson said. “This was a whole-genome analysis showing atypical nonhomologous on-target effects of genome editing. Of course this is a very different strategy from what we heard today, but, again, we have to know that this is safe.”

Despite the small sample size from the two highest-dose groups in the study, Dr. Watson said the investigators have reason for going forward. “I think the preclinical data supports moving forward, but the next studies will have to be scrutinized carefully,” she said. “This is a preventive therapy; the first tenet is to do no harm.”

Dr. Bellinger is an employee of Verve Therapeutics, which sponsored the trial. Dr. Watson disclosed relationships with Boehringer-Ingelheim, Amgen, Lilly and Novartis.

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