Single Ascending Dose Study of a Short Interfering RNA Targeting Lipoprotein(a) Production in Individuals With Elevated Plasma Lipoprotein(a) Levels

Abstract

ImportanceLipoprotein(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.ObjectivesTo 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 ParticipantsA 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.InterventionsParticipants 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 MeasuresThe 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.ResultsAmong 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 RelevanceIn 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 RegistrationClinicalTrials.gov Identifier: NCT04606602; EudraCT Identifier: 2020-002471-35

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“…Plasma Lp(a) levels were reduced by 46% at a dose of 30 mg, 86% at 100 mg, 96% at 300 mg, and 98% at 600 mg, as compared with the 10% with the placebo. Low-grade injection site reactions and headache were common treatment-emergent adverse events [ 119 ].…”

New Therapeutic Approaches in Treatment of Dyslipidaemia—A Narrative Review

“…The phase I trial of another siRNA molecule olpasiran showed a reduction in Lp(a) for over 90% and very few adverse effects compared with a reduction of up to 80% with pelacarsen in a phase II trial [ 46 , 47 ]. In a small phase I trial of the siRNA SLN360, which enrolled 32 participants with elevated Lp(a) levels and no known CVD, the maximal median percentage change from baseline in Lp(a) level over 150 days was observed: −10%, −46%, −86%, −96%, and −98% for the placebo group and the 30-mg, 100-mg, 300-mg, and 600-mg SLN360 groups, respectively [ 48 ].…”

Elevated lipoprotein(a) as a predictor for coronary events in older men

“…More recently, siRNA targeting LPA mRNA was trialed in a small study ( n = 32). A single dose of siRNA SLN360 was given to increase its selective uptake and concentration within hepatocytes, binding and degrading the apo(a) mRNA and reducing overall Lp(a) plasma levels for 150 days ( 30 ). With studies such as these highlighting the urgent need for Lp(a)-specific therapies, the current guidelines must still focus on managing and mitigating the risk associated with high Lp(a) levels prior to the need for intervention until a specific therapy is widely available ( 7 , 8 , 31 ).…”