Antisense Oligonucleotide Drug to Treat Elevated Triglycerides

Study Questions:

Can an N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA lower triglycerides and atherogenic lipoprotein levels?


AKCEA-APOCIII-LRx is a second-generation antisense oligonucleotide drug, which targets human APOC3 mRNA. The present study was a Phase 1/2a study to assess the safety, tolerability, and efficacy of AKCEA-APOCIII-LRx using a double-blind, placebo-controlled, dose-escalation study design. The participants were healthy volunteers, ages 18-65 years, with triglyceride levels ≥90 or ≥200 mg/dl. Single-dose cohorts were treated with 10, 30, 60, 90, and 120 mg subcutaneously, and multiple-dose cohorts were treated with 15 and 30 mg weekly subcutaneously for 6 weeks or 60 mg every 4 weeks subcutaneously for 3 months. Outcomes of interest included apoC-III and triglyceride levels and safety.


A total of 40 subjects were enrolled in the single ascending dose study and 37 subjects were enrolled in the multiple ascending dose study (17 weekly multiple dose group, and 10 every 4-week multiple dose group). In the single-dose cohorts treated with 10, 30, 60, 90, or 120 mg of AKCEA-APOCIII-LRx, median reductions of 0, -42%, -73%, -81%, and -92% in apoC-III, and -12%, -7%, -42%, -73%, and -77% in triglycerides were observed 14 days after dosing. In multiple-dose cohorts of 15 and 30 mg weekly and 60 mg every 4 weeks, median reductions of -66%, -84%, and -89% in apoC-III, and -59%, -73%, and -66% in triglycerides were observed 1 week after the last dose. Significant reductions in total cholesterol, apolipoprotein B, non-high-density lipoprotein cholesterol (HDL-C), very low-density lipoprotein cholesterol, and increases in HDL-C were also observed. AKCEA-APOCIII-LRx was well tolerated with one injection site reaction of mild erythema, and no flu-like reactions, platelet count reductions, liver, or renal safety signals.


The investigators concluded that treatment of hypertriglyceridemic subjects with AKCEA-APOCIII-LRx results in a broad improvement in the atherogenic lipid profile, with a favorable safety and tolerability profile.


As noted by the authors, further studies are warranted, in particular, among populations with cardiovascular disease risk factors such as diabetes and those with existing cardiovascular disease. Further safety evaluations in such populations are also warranted.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents

Keywords: Apolipoprotein C-III, Apolipoproteins B, Atherosclerosis, Cholesterol, LDL, Cholesterol, VLDL, Dyslipidemias, Erythema, Galactosamine, Lipoproteins, Oligonucleotides, Antisense, Primary Prevention, Risk Factors, RNA, Messenger, Triglycerides

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