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

Abstract

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.

Figure 1.. Flow of Participants Through the APOLLO Trial

^aNo further details were recorded in case report forms. The protocol specified exclusion for many conditions, including (but not limited to) any history of clinically overt cardiovascular disease, any uncontrolled or serious disease, moderate or severe hepatic cirrhosis, active serious mental illness, and positive nucleic acid test result for SARS-CoV-2. ^bWithdrawal prior to drug administration was a physician decision due to a clinically significant electrocardiogram finding recorded as an adverse event of sinus tachycardia.

Figure 2.. Primary Efficacy Outcome: Changes Over Time in Lipoprotein(a) Concentration

A, Lipoprotein(a) concentrations over time in the placebo group and each SLN360 dose group. The median lipoprotein(a) concentrations are shown as solid circles; the whiskers are IQRs for each of these values. The triangles are the mean concentrations at each time point. B, Percentage changes in lipoprotein(a) concentration over time for the placebo group and each SLN360 dose group. The median percentage changes in lipoprotein(a) concentration are shown as solid circles; the whiskers are IQRs for each of these values. The triangles are the mean percentage changes in concentration at each time point. In both panels, the median and mean values represent measurements in 6 patients for each treatment group except for the placebo group, which represents 8 participants. eFigures 2A and 2B in Supplement 3 show plots with individual data points.

Figure 3.. Secondary and Exploratory Outcomes: Changes in Low-Density Lipoprotein Cholesterol and Apolipoprotein B

A, Mean percentage changes in the secondary outcome, low-density lipoprotein cholesterol, over time in the placebo group and each SLN360 dose group. The mean percentage changes are shown as solid circles with the 95% CIs shown as whiskers. Baseline mean values for low-density lipoprotein cholesterol by dose group: placebo, 99 (SD, 48) mg/dL; 30-mg SLN360, 113 (SD, 38) mg/dL; 100-mg SLN360, 121 (SD, 46) mg/dL; 300-mg SLN360, 100 (SD, 25) mg/dL; 600-mg SLN360, 108 (SD, 54) mg/dL. B, Mean percentage changes in the exploratory outcome, apolipoprotein B, over time in the placebo group and each SLN360 dose group. The mean percentage changes are shown as solid circles with the 95% CIs shown as whiskers. Baseline mean values for apolipoprotein B by dose group: placebo, 81 (SD, 30) mg/dL; 30-mg SLN360, 83 (SD, 23) mg/dL; 100-mg SLN360, 94 (SD, 29) mg/dL; 300-mg SLN360, 89 (SD, 6) mg/dL; 600-mg SLN360, 81 (SD, 25) mg/dL. In both panels, the mean values represent measurements in 6 patients for each treatment group except for the placebo group, which represents 8 participants. Changes in total cholesterol contributed meaningfully to the main findings and are reported in eTable 3 in Supplement 3. Triglycerides and high-density lipoprotein cholesterol are not affected by changes in lipoprotein(a) and are not reported.