ACC 2022: Novel Gene-Silencing Therapy Cuts Lp(a) by 98%
Among the top-notch research presented at the American College of Cardiology 2022 Scientific Sessions was a small phase 1 trial that demonstrated big potential for a therapeutic that will lower lipoprotein [Lp(a)] and reduce atherosclerotic risk.
Lp(a) is a cholesterol-carrying, apolipoprotein B-containing lipoprotein that has an apolipoprotein(a) moiety attached. It is made mostly in the liver and has been shown to be an independent and causal risk factor for atherosclerotic cardiovascular diseases.
The APOLLO study tested SLN360 (Silence Therapeutics, London, UK), a short interfering RNA (siRNA) designed to reduce hepatic production of apolipoprotein(a).
APOLLO was a phase 1 dose-finding study and included 32 adults (mean age, 50 years; 53% female) with elevated plasma Lp(a) plasma concentrations (>150 nmol/L) but no known cardiovascular disease. The median baseline Lp(a) concentration was 224 nmol/L.
Participants were randomly assigned to a placebo or one of four SLN360 doses (30 mg, 100 mg, 300 mg, or 600 mg), all administered subcutaneously.
The maximal median change in Lp(a) was -89 nmol/L, -185 nmol/L, -268 nmol/L, and -227 nmol/L, in the 30-mg, 100-mg, 300-mg, and 600-mg SLN360 groups, respectively, as compared to -20 nmol/L in the placebo arm. This translated to (maximal median) percentage changes of -46%, -86%, -96%, and -98%, for the four ascending dose groups, respectively, as compared to -10% for placebo.
Five months after treatment, Lp(a) levels were still 71% to 81% below baseline, with evidence of a dose-dependent effect. In the highest dose groups, LDL-C was reduced between 20% to 25%.
The treatment was well tolerated, with the most common side effect being temporary soreness at the injection site.
“We thought it would work, but we were surprised by the magnitude and the duration of the effect,” said Steven E. Nissen, MD (Cleveland Clinic, Cleveland, OH), the study’s lead author. He noted that, historically, elevated Lp(a) has been thought of as “an untreatable abnormality” but new therapies are lowering the low-density lipoprotein-like moiety more effectively, allowing for absolute reductions previously not seen that researchers hope will provide clinical benefit.
“Whether these reductions can impact the incidence of ASCVD events or prevent progression of aortic stenosis remains to be determined, but optimism is warranted,” said Nissen.
The study was published simultaneously April 3, 2022, in JAMA, along with an Editorial Comment.
SLN360 is one of several new agents in development for the lowering of Lp(a), including an antisense oligonucleotide, pelacarsen, which has been shown to reduce Lp(a) plasma concentrations by up to 80% with weekly administration.