This year’s American Heart Association Scientific Sessions included groundbreaking trials in cardiometabolic therapeutics. Jianping Li, MD, presented primary results from a randomized, phase 2 trial of DR10624, a first-in-class agent in patients with severe hypertriglyceridemia. DR10624 has agonistic activity against fibroblast growth factor 21, glucagon, and glucagon-like peptide-1 receptors. The 12-week study of 3 escalating weekly doses vs placebo with 4 weeks of safety follow-up enrolled 79 mostly male Chinese individuals. DR10624 significantly reduced triglycerides, atherogenic lipids, and liver fat content with tolerable side effects. Although the results should be confirmed in longer trials in a more diverse population, they support further testing, including in individuals with metabolic dysfunction-associated steatohepatitis.
Results of a first-in-human phase 1 clinical trial of CTX310, a lipid nanoparticle CRISPR-Cas9 gene editing formulation targeting angiopoietin-like protein 3 (ANGPTL3) were presented by Stephen Nicholls, MBBS. ANGPTL3 regulates lipid metabolism through inhibition of lipoprotein and endothelial lipase. CTX310 induces permanent loss of function of the ANGPTL3 gene as a one-and-done treatment for elevated LDL-C and triglycerides. Loss-of-function gene variants for ANGPTL3 result in life-long reduced LDL-C and triglycerides, and decreased risk of atherosclerotic cardiovascular disease. A one-time treatment would address diminishing adherence to current lipid-lowering therapies. Single, escalating doses of CTX310 were administered to 15 mostly male participants with heterogeneous lipid parameters. The three highest doses reduced LDL-C about 50% and triglycerides about 55%. There was one death 179 days after treatment with the lowest dose deemed unrelated by the investigator. Results were simultaneously published in the New England Journal of Medicine. Efficacy seems durable at 2 to 6 months of follow-up. The results suggest the feasibility of assessment of efficacy in specific populations in future trials.
During a discussion at a press briefing where Dr. Nicholls’ coinvestigator Luke Laffin MD, presented the trial results, commenter Kiran Musunuru, MD, pointed out that there is an FDA-approved monoclonal antibody targeting ANGPTL3 (evinacumab) that requires life-long monthly infusions. Other less effective agents, that, like CTX310, target ANGPTL3 mRNA directly in the liver using short interfering RNA or oligonucleotides are in clinical trials, and also require repeated dosing. He called the CTX310 trial conceptually very attractive, and “in terms of efficacy the early results of the phase one clinical trial are a slam dunk. There's no question that this therapy works well.”
The day before the meeting started, one subject among more than 400 in another gene editing therapy trial died after severe liver injury a few weeks post-treatment. This therapy uses a similar lipid nanoparticle CRISPR Cas9 gene editor, although against a different target and in a different patient population, Dr. Musunuru said. Therefore, it’s possible a similar issue might arise with CTX310. “That’s why we do clinical trials. And that's why when going for a large indication with a common disease, like hyperlipidemia, a phase three clinical trial will need to enroll thousands of subjects to really be sure of the efficacy and safety.” He concluded by congratulating the investigators for an excellent and important study.
Dr. Lederman has no conflicts of interest to report.
Illustration by Diana Connolly
