RNA interference to control cardiovascular diseases

Lipoprotein(a) consists of a lipoprotein that contains apolipoprotein B and is covalently linked to apolipoprotein(a). Numerous epidemiological studies conducted over the past three decades have demonstrated an association between higher circulating lipoprotein(a) concentrations and increased risk of atherosclerotic cardiovascular disease. In addition, a growing number of Mendelian randomization and genomic association studies also support a Causal role of lipoprotein(a) in atherosclerosis and calcified aortic valve stenosis.

Although lipoprotein(a) is presumed, based on genetic data, to be a causative risk factor for atherosclerotic cardiovascular disease, none of the currently available drug therapies substantially reduce its concentrations. Plasma lipoprotein(a) concentration is determined primarily by genetics (approximately 70 to ≥90%),2, and its expression is controlled by the apolipoprotein(a) (LPA) gene.

Investigators at Brigham and Women’s Hospital, a founding member of the Mass General Brigham Health System, conducted a Phase 2, randomized, placebo-controlled clinical trial of olpasiran in patients with established cardiovascular disease to assess its safety and tolerability and to identify a dose olpasiran to reduce lipoprotein(a) levels.

The trial included 227 patients who received one of the four doses of olpasiran and 54 who received a placebo. They found that those who received the highest doses of olpasiran experienced a greater than 95% decrease in lipoprotein(a) over 36 weeks compared to the placebo. The treatment was not associated with any serious side effects, apart from occasional swelling at the injection site and other related minor reactions.

The results of this study demonstrate that a marked and sustained reduction in lipoprotein(a) is possible by RNA interference with olpasiran.

These numbers set the stage for a much larger Phase 3 trial to definitively test whether lowering lipoprotein(a) translates to better outcomes. Olpasiran is a very promising therapy for people with elevated levels who currently have no effective therapy to lower their concentration.

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