Elevated apolipoprotein C-III ( apoC-III ) levels are associated with hypertriglyceridaemia and coronary heart disease.
AKCEA-APOCIII-LRx is an N-acetyl galactosamine-conjugated antisense oligonucleotide targeted to the liver that selectively inhibits apoC-III protein synthesis.
The safety, tolerability, and efficacy of AKCEA-APOCIII-LRx was assessed in a double-blind, placebo-controlled, dose-escalation phase 1/2a study in healthy volunteers ( ages 18-65 ) with triglyceride levels greater than or equal to 90 or greater than or equal to 200 mg/dL.
Single-dose cohorts were treated with 10, 30, 60, 90, and 120 mg subcutaneously ( sc ) and multiple-dose cohorts were treated with 15 and 30 mg weekly sc for 6 weeks or 60 mg every 4 weeks sc for 3 months.
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.
In conclusion, treatment of hypertriglyceridaemic subjects with AKCEA-APOCIII-LRx resulted in a broad improvement in the atherogenic lipid profile with a favourable safety and tolerability profile. ( Xagena )
Alexander VJ et al, Eur Heart J 2019; 40: 2785-2796