A single intravenous dose of CTX310, an investigational CRISPR-Cas9 gene-editing therapy targeting the ANGPTL3 gene, produced substantial reductions in cholesterol and triglyceride levels in patients with refractory dyslipidemia, according to results from a phase 1 trial published in the New England Journal of Medicine.
Among 15 adults with uncontrolled hypercholesterolemia, hypertriglyceridemia, or mixed dyslipidemia despite maximally tolerated lipid-lowering therapy, the highest dose tested (0.8 mg/kg) reduced LDL cholesterol levels by a mean of 49% and triglyceride levels by 55% at 60 days in 4 participants. The therapy also reduced ANGPTL3 levels by 73% at 30 days among patients who received this dose. However, individual responses varied widely, with LDL reductions ranging from 19.5% to 86.6%.
The trial evaluated ascending doses of CTX310 ranging from 0.1 to 0.8 mg per kilogram. Participants received a single infusion and were followed for at least 60 days, with ongoing surveillance continuing. Lipid endpoints were assessed at 90 days for the 0.1–0.6 mg/kg cohorts and at 60 days for the 0.7–0.8 mg/kg cohorts. The median age was 53 years, 87% were male, and 40% had atherosclerotic cardiovascular disease. Baseline LDL cholesterol levels averaged 155 mg per deciliter, and median triglyceride levels were 192 mg per deciliter.
No dose-limiting toxic effects or serious adverse events related to CTX310 occurred. Infusion-related reactions were reported in 3 patients (20%), all of which were grade 2 in severity and resolved after pausing the infusion and administering supportive care. One of these 3 patients, who had elevated aminotransferase levels at baseline, experienced a transient elevation to 3 to 5 times baseline levels, peaking on day 4 and returning to baseline by day 14. No grade 3 or higher adverse events related to CTX310 were observed.
One death occurred 179 days after treatment with the lowest dose (0.1 mg per kilogram). A second serious adverse event involved a spinal disk herniation 7 months after treatment at 0.3 mg per kilogram. Neither event was determined to be related to CTX310.
CTX310 consists of lipid-nanoparticle–encapsulated CRISPR-Cas9 messenger RNA and guide RNA targeting hepatic ANGPTL3 to induce a loss-of-function mutation in liver cells. ANGPTL3 inhibits lipoprotein and endothelial lipases, and naturally occurring loss-of-function variants in ANGPTL3 are associated with reduced LDL cholesterol and triglyceride levels and decreased cardiovascular disease risk.
The reductions in atherogenic lipoproteins observed with CTX310 are similar to those seen with evinacumab, a monoclonal antibody targeting ANGPTL3 approved for homozygous familial hypercholesterolemia. However, CTX310 aims to provide durable, potentially permanent genetic modification after a single treatment—though long-term durability has not yet been established and will require extended follow-up. The study authors noted that variability in response may be influenced by factors including hepatic steatosis, inflammation, and individual genetic and metabolic profiles.
Researchers acknowledged several limitations, including the small sample size, open-label design, heterogeneous patient population, and short follow-up duration relative to the intended permanence of the genetic modification. The trial enrolled predominantly White male participants from 6 sites in Australia, New Zealand, and the United Kingdom. Longer follow-up in larger populations is needed to assess late-emerging safety signals and durability of lipid lowering. Current Food and Drug Administration guidance recommends follow-up for up to 15 years after gene-editing drug administration.
"Editing of ANGPTL3 was associated with few adverse events and resulted in reductions from baseline in ANGPTL3 levels," wrote lead study authors Luke J. Laffin, MD, of Cleveland Clinic Foundation, and Stephen J. Nicholls, MB, BS, PhD, of Monash University, and colleagues.
The study was funded by CRISPR Therapeutics. Full author disclosures can be found in the published study.
Source: New England Journal of Medicine
