Gene Editing for Lipids: 1-Year CTX310 Data, With Luke Laffin, MD

A single infusion of CTX310, an investigational in vivo CRISPR-Cas9 gene-editing therapy targeting ANGPTL3, produced durable reductions in ANGPTL3, LDL cholesterol, and triglycerides through 1 year of follow-up in a phase 1a trial, according to data presented at the European Society of Cardiology (ESC) Congress 2026 and published simultaneously in the New England Journal of Medicine.¹

Luke Laffin, MD, principal investigator and medical director of the Cleveland Clinic Coordinating Center for Clinical Research, discussed the findings with HCPLive.

"What we did was describe the durability of CTX-310 throughout the course of the study. This builds upon data that was presented at the American Heart Association in November of 2025, which showed ANGPTL3 reduction at day 30 and lipid biomarkers at the highest dose at day 60," Laffin said. "Now we have 12-month data for all participants who received gene editing via CRISPR-Cas9 with CTX310."

CTX310 Phase 1a Durability Data at 1 Year

The phase 1a portion of the open-label, dose-escalation trial was conducted in Australia and New Zealand, enrolling 15 adults with uncontrolled hypercholesterolemia, moderate to severe hypertriglyceridemia, or mixed dyslipidemia between May 2024 and August 2025. Participants received a single intravenous dose of CTX310 at 1 of 5 levels, ranging from 0.1 to 0.8 mg/kg lean body weight, across cohorts with homozygous or heterozygous familial hypercholesterolemia, severe hypertriglyceridemia, or mixed dyslipidemia.¹ Most participants were on background statins or ezetimibe, and 40% were taking PCSK9 inhibitors.²

Among the 4 participants who received the highest dose (0.8 mg/kg), the mean percent change from baseline at 1 year was -78.6% in ANGPTL3 (range, -89.0 to -63.1), -52.5% in LDL cholesterol (range, -84.2 to -24.4), and -47.8% in triglycerides (range, -77.6 to -14.7). Across the full highest-dose cohort, ANGPTL3 reductions reached up to 89%, with a mean reduction of 79% sustained at 1 year, alongside mean reductions of 52.0% in non-HDL cholesterol and 37.2% in apolipoprotein B.²

Asked how clinicians should interpret the variability in response among the 4 highest-dose participants, Laffin cautioned against overreading small numbers: “When you have small numbers, like four patients, there's going to be some variability... the means are really sort of a starting point, and then we have to do larger studies to really understand whether the response to CTX-310 is heterogeneous between the people that have severe hypertriglyceridemia versus those that have HeFH versus those with mixed dyslipidemia," Laffin said. "We enrolled a very broad population because when you do a first-in-human trial, you want to get anyone that you can to show the safety, and then the next step is really looking at the efficacy in these more dedicated cohorts."

Interpreting Variability, Safety, and What Comes Next for CTX310

The trial's primary endpoint was adverse events, including dose-limiting toxic effects, and no dose-limiting toxicity was reported through 1 year.¹ A pair of previously reported serious adverse events were assessed as unrelated to CTX310, with one subsequently determined to be a preexisting condition, and no new serious adverse events or adverse events of special interest occurred during extended follow-up.¹ Beyond a transient aminotransferase elevation in 1 participant shortly after treatment, no additional liver-function abnormalities occurred, and infusion-related reactions in 3 participants were grade 2 and resolved.²

Laffin said the data support advancing the program, though not yet a large outcomes study. "I don't think anyone's saying, based on this, we should start doing a 10,000-patient outcome study, but it's clearly enough to move into phase 2 to understand really what the effect is and the safety," Laffin said. "I think that at this point, we’re very confident that it looks safe."

On what would constitute a convincing efficacy signal in the next phase, Laffin said the relevant endpoints depend on the patient cohort: LDL cholesterol and apolipoprotein B for patients with familial hypercholesterolemia, triglycerides for those with severe hypertriglyceridemia, and both for mixed dyslipidemia. Asked when persistence at 1 year might be called permanence, Laffin noted participants have consented to 15-year follow-up, but cautioned drop-in of other lipid therapies over time complicates any such determination; he described the on-target ANGPTL3 effect as a convincing signal, though larger, longer-term studies in more patients are still needed before durability can be called permanent.

CRISPR Therapeutics is now evaluating a fixed 0.8 mg/kg dose of CTX310 in a phase 1b trial in patients with refractory dyslipidemias, with an update from the severe hypertriglyceridemia cohort expected in the second half of 2026. The company's broader in vivo cardiovascular gene-editing portfolio also includes CTX340, targeting angiotensinogen for refractory hypertension, and CTX321, targeting LPA for elevated lipoprotein(a).¹

Editors’ note: Laffin reports relevant disclosures with AstraZeneca, Arrowhead, Medtronic, Eli Lilly, Mineralys, Crispr Therapeutics, Novartis, Novo Nordisk, and others.

References

1. Laffin L, et al. Durability of CRISPR-Cas9 gene editing targeting ANGPTL3 with CTX310. N Engl J Med. 2026. Presented at: ESC Congress 2026; August 28, 2026; Munich, Germany.

2. CRISPR Therapeutics. CRISPR Therapeutics presents phase 1a data for CTX310 demonstrating deep and durable ANGPTL3 editing, triglyceride and LDL lowering at ESC Congress 2026. Published August 28, 2026. Accessed August 30, 2026. https://ir.crisprtx.com/news-releases/news-release-details/crispr-therapeutics-presents-phase-1a-data-ctx310r-demonstrating