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Updated: Sep 28, 2025
Isolation of High-density Lipoproteins for Non-coding Small RNA Quantification
Published on: November 28, 2016
Single Ascending Dose Study of a Short Interfering RNA Targeting Lipoprotein(a) Production in Individuals With
Steven E Nissen1, Kathy Wolski1, Craig Balog1
1Cleveland Clinic Center for Clinical Research, Cleveland, Ohio.
Importance:
Lipoprotein(a) (Lp[a]) is an important risk factor for atherothrombotic cardiovascular disease and aortic stenosis, for which there are no treatments approved by regulatory authorities.
Objectives:
To assess adverse events and tolerability of a short interfering RNA (siRNA) designed to reduce hepatic production of apolipoprotein(a) and to assess associated changes in plasma concentrations of Lp(a) at different doses.
Design, Setting, And Participants:
A single ascending dose study of SLN360, an siRNA targeting apolipoprotein(a) synthesis conducted at 5 clinical research unit sites located in the US, United Kingdom, and Australia. The study enrolled adults with Lp(a) plasma concentrations of 150 nmol/L or greater at screening and no known clinically overt cardiovascular disease. Participants were enrolled between November 18, 2020, and July 21, 2021, with last follow-up on December 29, 2021.
Interventions:
Participants were randomized to receive placebo (n = 8) or single doses of SLN360 at 30 mg (n = 6), 100 mg (n = 6), 300 mg (n = 6), or 600 mg (n = 6), administered subcutaneously.
Main Outcomes And Measures:
The primary outcome was evaluation of safety and tolerability. Secondary outcomes included change in plasma concentrations of Lp(a) to a maximum follow-up of 150 days.
Results:
Among 32 participants who were randomized and received the study intervention (mean age, 50 [SD, 13.5] years; 17 women [53%]), 32 (100%) completed the trial. One participant experienced 2 serious adverse event episodes: admission to the hospital for headache following SARS-CoV-2 vaccination and later for complications of cholecystitis, both of which were judged to be unrelated to study drug. Median baseline Lp(a) concentrations were as follows: placebo, 238 (IQR, 203-308) nmol/L; 30-mg SLN360, 171 (IQR, 142-219) nmol/L; 100-mg SLN360, 217 (IQR, 202-274) nmol/L; 300-mg SLN360, 285 (IQR, 195-338) nmol/L; and 600-mg SLN360, 231 (IQR, 179-276) nmol/L. Maximal median changes in Lp(a) were -20 (IQR, -61 to 3) nmol/L, -89 (IQR, -119 to -61) nmol/L, -185 (IQR, -226 to -163) nmol/L, -268 (IQR, -292 to -189) nmol/L, and -227 (IQR, -270 to -174) nmol/L, with maximal median percentage changes of -10% (IQR, -16% to 1%), -46% (IQR, -64% to -40%), -86% (IQR, -92% to -82%), -96% (IQR, -98% to -89%), and -98% (IQR, -98% to -97%), for the placebo group and the 30-mg, 100-mg, 300-mg, and 600-mg SLN360 groups, respectively. The duration of Lp(a) lowering was dose dependent, persisting for at least 150 days after administration.
Conclusions And Relevance:
In this phase 1 study of 32 participants with elevated Lp(a) levels and no known cardiovascular disease, the siRNA SLN360 was well tolerated, and a dose-dependent lowering of plasma Lp(a) concentrations was observed. The findings support further study to determine the safety and efficacy of this siRNA.
Trial Registration:
ClinicalTrials.gov Identifier: NCT04606602; EudraCT Identifier: 2020-002471-35.
Insights
The siRNA SLN360 demonstrated good tolerability and effectively lowered lipoprotein(a) levels in adults with elevated Lp(a). Further research is warranted to confirm the safety and efficacy of this treatment for cardiovascular disease risk reduction.
Area of Science:
- Cardiovascular Science
- Pharmacology
- Genetics
Background:
- Lipoprotein(a) (Lp[a]) is a significant risk factor for cardiovascular diseases like atherothrombotic disease and aortic stenosis.
- Currently, no approved treatments exist to target Lp(a) for risk reduction.
Purpose of the Study:
- To evaluate the safety and tolerability of SLN360, an siRNA targeting apolipoprotein(a) production.
- To assess the dose-dependent impact of SLN360 on plasma Lp(a) concentrations.
Main Methods:
- A single ascending dose, randomized, placebo-controlled Phase 1 study involving 32 adults with elevated Lp(a) levels.
- Participants received subcutaneous SLN360 at doses of 30 mg, 100 mg, 300 mg, or 600 mg, or placebo.
- Safety, tolerability, and changes in plasma Lp(a) concentrations were monitored for up to 150 days.
Main Results:
- SLN360 was well-tolerated across all tested doses, with no serious adverse events attributed to the drug.
- A dose-dependent reduction in plasma Lp(a) was observed, with maximal reductions up to 98% at higher doses.
- Lp(a) lowering effects persisted for at least 150 days, demonstrating sustained impact.
Conclusions:
- The siRNA SLN360 shows promising safety and efficacy in reducing Lp(a) levels in individuals with elevated Lp(a).
- These findings support further clinical investigation into SLN360 for the prevention of cardiovascular events.
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