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

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

News - Nov. 14, 2023

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

  • There was a dose-dependent reduction in the median Lp(a) level in all lepodisiran treatment groups, whereas the placebo group showed only minimal Lp(a) change over time.
  • For example, in the group with the highest lepodisiran dose (608 mg), the median Lp(a) level was below the lower limit of quantitation by day 29 and remained unmeasurable for the next 9 months. At 48 weeks, the Lp(a) reduction in this group was 94%.
  • Treatment-emergent adverse events, including headache and rhinorrhea, were mild. In both the lepodisiran and placebo groups, low-grade, transient injection site reactions were reported.
  • There were also no major laboratory abnormalities that differed between the lepodisiran and placebo groups.


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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