Among patients with elevated lipoprotein(a) (Lp[a]) levels and no known cardiovascular disease, the short interfering RNA (siRNA) agent SLN360 was well tolerated, with a dose-dependent lowering of plasma Lp(a) concentrations occurring, according to the results of a study published in JAMA.
The phase 1 APOLLO trial (ClinicalTrials.gov Identifier: NCT04606602) evaluated the tolerability of SLN360 after a single dose and measured Lp(a) concentrations up to 150 days following administration of the agent.
Adults aged 18 years and older with no known atherosclerotic cardiovascular disease, an Lp(a) concentration ≥150 nmol/L (approximately >60 mg/dL), and a body mass index of 18 to 45 kg/m2 were eligible to participate in the study. The study was conducted at 5 international clinical research units, and patients were enrolled from November 18, 2020, to July 21, 2021, with the last follow-up evaluation occurring on December 29, 2021.
The participants were grouped into 4 ascending single-dose cohorts and randomly assigned to SLN360 30 mg, 100 mg, 300 mg, or 600 mg, or placebo (sodium chloride, 0.9%) administered by subcutaneous injection in the abdomen. The primary outcome of interest was safety and tolerability of SLN360.
A total of 32 participants (mean age, 50 [SD 13.5] years; 47% men) were included. Median baseline Lp(a) concentrations were 238 (interquartile range [IQR], 203-308) nmol/L, 171 (IQR, 142-219) nmol/L, 217 (IQR, 202-274) nmol/L, 285 (IQR, 195-338) nmol/L, and 231 (IQR, 179-276) nmol/L for the placebo group and the 30-mg, 100-mg, 300-mg, and 600-mg SLN360 groups, respectively.
Participants’ 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 for the placebo group and the 30-mg, 100-mg, 300-mg, and 600-mg SLN360 groups, respectively.
The maximal median percentage changes were -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.
Post-hoc analysis demonstrated that median Lp(a) concentrations were >70% and >80% below baseline 150 days after administration of the 300-mg and 600-mg SLN360 doses, respectively.
Administration of SLN360 resulted in a dose-dependent decrease in total cholesterol and low-density lipoprotein cholesterol (LDL-C). Mean levels decreased by a maximum of 18% for total cholesterol and 26% for LDL-C, with both occurring after the 600-mg SLN360 dose.
Study limitations include the small sample size, inclusion of participants without known cardiovascular disease, and the limited ability to assess the safety of SLN360. In addition, the cohort may not reflect results for this therapy in a more diverse population.
“The siRNA SLN360 was well tolerated, and a dose-dependent reduction in plasma Lp(a) levels was observed,” stated the investigators. “The findings support further study to determine the safety and efficacy of this siRNA.”
Disclosure: The trial was funded by Silence Therapeutics PLC and coordinated by Silence Therapeutics, Medpace, and C5Research. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Nissen SE, Wolski K, Balog C, et al. Single ascending dose study of a short interfering RNA targeting lipoprotein(a) production in individuals with elevated plasma lipoprotein(a) levels. JAMA. Published online April 3, 2022. doi:10.1001/jama.2022.5050