RNA therapeutics
SLN360 sustains up to 95% Lp(a) reduction for at least 9 weeks in cynomolgus monkeys, preclinical data ahead of human trials (Atherosclerosis 2022)
Original title: Pre-clinical assessment of SLN360, a novel siRNA targeting LPA, developed to address elevated lipoprotein (a) in cardiovascular disease
In preclinical studies, SLN360, a GalNAc-conjugated siRNA targeting LPA, potently reduced LPA mRNA in primary human and cynomolgus hepatocytes in vitro without affecting APOB or PLG expression. In cynomolgus monkeys given single or multiple subcutaneous doses (0.1-9.0 mg/kg), SLN360 exposure peaked at 2 hours with near-full elimination by 24 hours, and produced LPA mRNA reduction of up to 91% at 2 weeks, with only the 3 mg/kg group showing appreciable return toward baseline (40%) by the study end. Serum Lp(a) reduction of up to 95% was observed, lasting at least 9 weeks and peaking at day 21, with a minimally effective dose of 0.3 mg/kg and an ED50 of 0.6 mg/kg. No consistent dose- or time-dependent liver lipid accumulation was observed. The findings support SLN360 potential as a durable Lp(a)-lowering therapy ahead of clinical development.
Original abstract
Background And Aims: The LPA gene encodes apolipoprotein (a), a key component of Lp(a), a potent risk factor for cardiovascular disease with no specific pharmacotherapy. Here we describe the pharmacological data for SLN360, a GalNAc-conjugated siRNA targeting LPA, designed to address this unmet medical need.
Methods: SLN360 was tested in vitro for LPA knockdown in primary hepatocytes. Healthy cynomolgus monkeys received single or multiple subcutaneous doses of the SLN360 sequence ranging from 0.1 to 9.0 mg/kg to determine the pharmacokinetic and pharmacodynamic effects. Liver mRNA and serum biomarker analyses were performed.
Results: In vitro, the SLN360 sequence potently reduces LPA mRNA in primary cynomolgus and human hepatocytes, while no effect was observed on the expression of APOB or PLG. In vivo, SLN360 exposure peaks 2 h after subcutaneous injection with near full elimination by 24 h. Specific LPA mRNA reduction (up to 91% 2 weeks after dosing) was observed with only the 3 mg/kg group showing appreciable return to baseline (40%). No consistent dose- or time-dependent effect on the expression of APOB, PLG or a panel of sensitive markers of liver lipid accumulation was observed. Potent (up to 95%) and long lasting (≥9 weeks) serum Lp(a) reduction was observed, peaking in all active groups at day 21. The minimally effective dose was determined to be 0.3 mg/kg with an ED50 of 0.6 mg/kg.
Conclusions: SLN360 induces a sustained reduction in serum Lp(a) levels in cynomolgus monkeys following subcutaneous dosing. SLN360 has potential to address the unmet need of Lp(a) reduction in cardiovascular diseases.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.