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PHILADELPHIA -- A DNA base editing therapy, intended for lifelong lowering of LDL cholesterol, passed initial tests in people with severe, advanced atherosclerotic cardiovascular disease (ASCVD).

According to interim results of the heart-1 proof-of-concept study, the 10 participants with heterozygous familial hypercholesterolemia (HeFH) showed dose-dependent reductions in blood PCSK9 protein and LDL cholesterol after getting the VERVE-101 CRISPR therapy, reported Andrew Bellinger, chief scientific officer of Verve Therapeutics.

In the single patient receiving the highest dose of the gene editing therapy, LDL cholesterol fell by 55% and blood PCSK9 protein level went down by 47%. LDL reduction stayed durable out to 6 months in this individual, Bellinger said at the American Heart Association (AHA) annual meeting.

Bellinger called VERVE-101 gene editing a one-time "molecular surgery without a scalpel." Although it is being tested first in the high-risk population of HeFH -- an inherited disease characterized by lifelong severe elevations in LDL cholesterol starting at a young age -- this medicine may ultimately have a role in a wider pool of patients, he suggested during a press conference

"If you think about where a gene editing therapy could really fit into the landscape, I think it really is ideal for patients who need long term decades of treatment. Not necessarily the patient who is 69 and had a heart attack last week. So we're envisioning that this will ultimately be a treatment that could be applied earlier in the disease course to younger patients who have very high lifetime risks, but not necessarily high risk over the next year or 2 or even 10 years," Bellinger said.

Safety and tolerability are the major questions surrounding VERVE-101. Bellinger announced that the next steps are to enroll higher-dose cohorts (0.45 and 0.6 mg/kg) and finish the dose escalation phase of the heart-1 trial. Plus, he said, there will be an expansion cohort that starts enrolling in 2024, and a placebo-controlled phase II trial commencing in 2025.

Study Details

A second-generation CRISPR technology, VERVE-101 is an investigational DNA base editing medicine that is delivered via one IV infusion into blood through lipid nanoparticles. Targeted inside hepatocytes, an editor protein and guide then locate the PCSK9 gene, where they perform a single base pair change to permanently turn off PCSK9 production in that liver cell and presumably dampen downstream cholesterol production.

Bellinger argued that long-term risks of PCSK9 gene editing are unlikely given the safety of PCSK9 knockdown previously demonstrated with other strategies such as monoclonal antibodies.

Monoclonal antibodies had emerged as a new class of lipid-lowering PCSK9 inhibitors with the 2015 FDA approval of alirocumab (Praluent) for lowering LDL cholesterol in people with HeFH or clinical ASCVD. Approval for evolocumab (Repatha) followed quickly that year. For both PCSK9 inhibitors, the problem is not so much safety or efficacy but access -- given their high price-tags and need to inject antibodies every 2 weeks.

Last year, FDA approved inclisiran (Leqvio) as the first small interfering RNA (siRNA) therapy for lowering LDL cholesterol. Inclisiran injections are administered twice yearly, already a more convenient alternative to the monoclonal antibodies. In trials, temporary injection site reactions have been the main safety events of note for this siRNA.

Press conference moderator Donald Lloyd-Jones, MD, of Northwestern University Feinberg School of Medicine in Chicago, remarked on residual risks remaining in patients despite the renaissance in therapies for lipid disorders in the last decade.

As such, cardiovascular disease remains the in the U.S.

Heart-1 is planned to last 1 year and FDA is requiring long-term follow-up of another 14 years to assess the safety and efficacy of VERVE-101 gene editing.

A Game Changer?

"You're changing the genome forever. 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 can be revolutionary, but we have to make sure it's safe. And regarding the outcomes, we just don't know," said Karol Watson, MD, PhD, of the University of California Los Angeles, during the press conference.

"I think the preclinical data does support moving forward. And I think that next studies will absolutely have to be scrutinized so carefully for safety," she urged.

Bellinger reported that two participants who got the VERVE-101 treatment at different doses had a total of three cardiovascular events:

• One fatal cardiac arrest 5 weeks after infusion (0.3 mg/kg)
• One myocardial infarction (MI) occurred day after infusion (0.45 mg/kg)
• That MI survivor then had a non-sustained ventricular tachycardia (NSVT) over a month after infusion

Investigators determined the MI as potentially related to the treatment, but not the NSVT.

Bellinger also acknowledged the risk of off-target editing elsewhere in the genome. "I think really the risk there is probably developing cancer. You know, that's where we put 95% of our work as a company is to demonstrating that we do not induce structural arrangements, we do not make edits elsewhere in the genome. And so we think that risk is very low."

Lloyd-Jones suggested additional caution regarding inflammation associated with the VERVE-101 injection that may have some short-term effects.

Nevertheless, he said it would be "the dream for me as a clinician" to have something like this for a 20-year-old with HeFH who would otherwise be "looking at a lifetime of taking a statin pill every single day, or they could have an MI at age 32."

For now, heart-1 is continuing enrollment at multiple sites in the U.K. and New Zealand.

The present interim report described the 10 people who received one of four doses (ranging from 0.1 mg/kg to 0.6 mg/kg) in the first-in-human phase Ib study of VERVE-101. Eligible participants were people with HeFH and high risk for cardiovascular events.

The interim study cohort averaged age 54, with eight out of 10 being men. Mean screening LDL cholesterol was 193 mg/dL, and nine out of the 10 people had a known LDLR mutation causing their HeFH. Nearly all participants had undergone prior coronary revascularization and were on statin therapy.