Physicians' Academy for Cardiovascular Education

Phase 1 trial results of extended duration siRNA targeting Lp(a)

News - Nov. 14, 2023

Efficacy and Safety of Lepodisiran: An Extended Duration Short-Interfering RNA Targeting Lipoprotein (a)

Presented at the AHA Scientific Sessions 2023 by: Steven Nissen, MD- Cleveland, OH, USA

Introduction and methods

Lp(a) is an LDL-like lipoprotein particle composed of apolipoprotein(a) (apo(a)) that is covalently bound to apoB-100. Lepodisiran is a small -interfering RNA molecule that lowers circulating Lp(a) levels by degrading the mRNA encoding for apo(a). The nucleotides of the anti-sense strand of lepodisiran are chemically modified to resist degradation by ribonuclease to prolong its duration of action. The aim of this phase 1 trial was to assess the safety and efficacy of lepodisiran in individuals with elevated Lp(a) levels.

This was a multicenter, single-ascending dose, placebo-controlled, phase 1 RCT conducted in the USA and Singapore in which 48 participants with no known CVD but with Lp(a) levels ≥75 nmol/L (≥30 mg/dL) were randomized to a single subcutaneous dose of lepodisiran (4, 12, 32, 96, 304, or 608 mg; n=6 in each group) or placebo (n=12).

The primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and the change in serum Lp(a) level from baseline to a maximum of 337 days (48 weeks).

Main results


This placebo-controlled phase 1 trial in participants with elevated Lp(a) levels showed that subcutaneous injection of a single dose of lepodisiran resulted in dose-dependent reductions of serum Lp(a) level (up to 94% at 48 weeks) and was well-tolerated. A phase 2 multidose trial is currently underway.

- Our reporting is based on the information provided at the AHA Scientific Sessions 2023 -

Watch a video by Steven Nissen on lepodisiran The results of this study were simultaneously published in JAMA.

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