Early study suggests gene editing can lower LDL cholesterol via PCSK9 inhibition
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Key takeaways:
- A single-dose CRISPR gene-editing infusion lowered blood PCSK9 in three patients with HeFH and advanced CAD.
- One patient who received the highest dose had LDL lowered 55% at 6 months.
PHILADELPHIA — A novel single-dose CRISPR base-editing infusion for patients with heterozygous familial hypercholesterolemia and advanced CAD reduced serum PCSK9 and lowered LDL by up to 55% in one patient, a speaker reported.
The interim results of the small, first-in-human, phase 1b heart-1 trial assessing the safety and efficacy of VERVE-101 (Verve Therapeutics) for the treatment of heterozygous familial hypercholesterolemia (HeFH) were presented at the American Heart Association Scientific Sessions.
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“With [HeFH], the current care consists of daily pills and intermittent injections that must be taken for decades,” Andrew M. Bellinger, MD, PhD, chief scientific officer at Verve Therapeutics in Boston, said during a press conference. “Under this model, very few patients reach goal — only 22% in the U.S. and 3% globally. This chronic care model seems to be broken. Human genetics suggests a potential solution — turning off the cholesterol-raising PCSK9 gene in the liver to durably lower cholesterol. Naturally occurring gene variants exist. Certain individuals carry naturally occurring gene variants that confer lifelong LDL lowering and dramatic protection against [atherosclerotic] CVD. We asked the question: Can we develop a single-course treatment that mimics these naturally occurring variants and protects against ASCVD?”
Bellinger and colleagues designed VERVE-101, a novel CRISPR base-editing medicine, to deactivate hepatic PCSK9 with a single DNA base-pair change and, as a result, lower LDL, according to the presentation.
“It’s a lipid nanoparticle encapsulating two RNA molecules: an mRNA for an adenine-based editor ... and a guide RNA for PCSK9,” Bellinger said during the press conference.
Bellinger said the particle has a three-step mechanism of action:
- The drug is administered via infusion as a lipid nanoparticle and is taken up by hepatocytes in the liver by the LDL receptor.
- Once inside, the adenine-based editor protein is produced and the guide, RNA and the protein together find the PCSK9 gene in the nucleus.
- The single DNA base-pair change is made at one position in the PCSK9 gene to turn off PCSK9 production by that liver cell.
The heart-1 trial was an open-label proof-of-concept study in which 10 participants with HeFH (mean age, 54 years; 80% men) received single peripheral IV infusion of VERVE-101 over several hours across four dose cohorts: 0.1 mg/kg, 0.3 mg/kg, 0.45 mg/kg and 0.6 mg/kg.
All participants had preexisting obstructive CAD requiring revascularization and three were not tolerant to high-intensity statins.
At baseline, mean LDL was 193 mg/dL and nine participants reached at least 28 days of follow-up.
One participant in the 0.45 mg/kg dose group was lost to follow-up.
From 28 days through last available follow-up, serum PCSK9 levels decreased 47% to 84% among the three participants in the two highest-dose groups, according to the presentation.
PCSK9 reduction conferred an LDL reduction of 39% to 55% in the two highest-dose cohorts, and the 55% reduction seen in the highest-dose administration of VERVE-101 was durable out to 180 days.
The researchers reported three treatment-related serious adverse events of grade 3 or higher in two patients: one experienced a fatal cardiac arrest approximately 5 weeks after infusion and the other experienced MI and nonsustained ventricular tachycardia. However, an independent data and safety monitoring board determined that these events were consistent with a patient population with advanced ASCVD and recommended continued VERVE-101 dosing; the DSMB deemed the fatal cardiac arrest and the nonsustained ventricular tachycardia to be unrelated to the treatment, and the MI to be potentially related to the treatment due to the proximity to dosing, according to the presentation.
“The next steps for the study are that we’re enrolling more patients in the 0.45 mg/kg and 0.6 mg/kg cohort and plan to enroll larger studies, expansion cohorts and a randomized placebo-controlled study in 2025,” Bellinger said during the press conference. “The heart-1 trial demonstrated the first human proof-of-concept for in vivo DNA base editing. We saw dose-dependent reductions in blood LDL and blood PCSK9, and those reductions were clinically meaningful. ... The safety profile supports continued development.”
Perspective
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Karol E. Watson, MD, PhD, FNLA, FACC, FAHA
This was a perfect proof-of-principle study. We learned that we get durable LDL lowering with the gene editing strategy.
This has never been done before. The drug itself, we learned, can give us this durable strategy. But as it has been mentioned, this is a gene editing study. You are changing the genome forever. Safety is going 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 it's safe.
Regarding the outcomes, we just don't know. This early study showed us that we could do this, but we'll have to see if it's safe and if there's efficacy in terms of what we really care about: the CV outcomes.
In a study that came out in PNAS earlier this year [Tsai HH, et al. Nat Commun. 2023;doi:10.1038/s41467-023-40901-x], there are concerns about gene editing. This was an analysis looking at whole genome analysis showing atypical non-homologous off-target effects of gene editing.
Of course, this is a very different strategy than what we heard today, but again, we have to know that this is safe.
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Bellinger A, et al. LBS.06. Future of lipid-lowering therapy: Novel mechanisms and approaches. Presented at: American Heart Association Scientific Sessions; Nov. 11-13, 2023; Philadelphia.
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