Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study

Area of Science:

• Cardiovascular Pharmacology
• Drug Development
• Lipid Metabolism

Background:

• Elevated lipoprotein(a) (Lp[a]) is a significant risk factor for cardiovascular disease and calcific aortic valve stenosis.
• Currently, no effective therapies exist to reduce plasma Lp(a) concentrations.
• ISIS-APO(a)Rx is a novel antisense drug targeting apolipoprotein(a) (apo[a]) synthesis in the liver.

Purpose of the Study:

• To evaluate the safety, pharmacokinetics, and pharmacodynamics of ISIS-APO(a)Rx.
• To assess the efficacy of ISIS-APO(a)Rx in reducing plasma Lp(a) concentrations in healthy adults.

Main Methods:

• A randomized, double-blind, placebo-controlled, phase 1 study involving healthy adults aged 18-65 years with elevated Lp(a).
• Participants received single subcutaneous injections or multiple doses of ISIS-APO(a)Rx (50-400 mg) or placebo.
• Primary endpoint was the percentage change in Lp(a) concentration from baseline at 30 or 36 days; safety and tolerability were also assessed.

Main Results:

• Multi-dose ISIS-APO(a)Rx (100-300 mg) demonstrated dose-dependent reductions in plasma Lp(a) concentrations, with decreases of up to 77.8% at 300 mg (p<0.001).
• Reductions in oxidized phospholipids associated with apoB-100 and apo(a) were also observed.
• Mild injection site reactions were the most frequent adverse events.

Conclusions:

• ISIS-APO(a)Rx achieves potent, dose-dependent, and selective reductions in plasma Lp(a).
• The drug's safety and tolerability profile support its further clinical development.
• ISIS-APO(a)Rx shows promise as a therapeutic agent for reducing cardiovascular disease and calcific aortic valve stenosis risk in individuals with high Lp(a).