Lepodisiran, an Extended-Duration Short Interfering RNA Targeting Lipoprotein(a): A Randomized Dose-Ascending...

Area of Science:

• Cardiovascular Medicine
• Pharmacology
• RNA Therapeutics

Background:

• Elevated lipoprotein(a) is a heritable risk factor for atherosclerotic disease and aortic stenosis.
• Current therapeutic options for reducing lipoprotein(a) are limited, highlighting the need for novel pharmacological interventions.

Purpose of the Study:

• To evaluate the safety, tolerability, pharmacokinetics, and efficacy of lepodisiran, a short interfering RNA targeting apolipoprotein(a) synthesis, in individuals with elevated lipoprotein(a).
• To assess the dose-dependent effects of single lepodisiran administrations on serum lipoprotein(a) concentrations.

Main Methods:

• A Phase 1, single ascending-dose, randomized, placebo-controlled trial involving 48 adults with elevated lipoprotein(a) levels.
• Participants received subcutaneous placebo or lepodisiran at doses ranging from 4 mg to 608 mg.
• Safety, tolerability, plasma lepodisiran levels, and changes in lipoprotein(a) concentrations were monitored up to 336 days.

Main Results:

• Lepodisiran was generally well-tolerated across all tested doses.
• Pharmacokinetic analysis showed lepodisiran plasma levels peaked within 10.5 hours and were undetectable by 48 hours.
• A dose-dependent reduction in lipoprotein(a) was observed, with the highest dose (608 mg) achieving a median reduction of 97% at day 337.

Conclusions:

• Single doses of lepodisiran demonstrated favorable safety and tolerability profiles in individuals with elevated lipoprotein(a).
• The drug induced significant, dose-dependent, and long-lasting reductions in serum lipoprotein(a) concentrations.
• These findings provide a strong rationale for further investigation of lepodisiran in clinical trials for cardiovascular risk management.