APOLLO: Short Interfering RNA Shows Promise for Reducing Lipoprotein(a)

A single ascending dose of SLN360, a short interfering RNA (siRNA), shows promise in lowering plasma lipoprotein(a) concentrations in patients with elevated lipoprotein(a) levels and no known cardiovascular disease, based on results from the phase 1 APOLLO trial presented April 3 at ACC.22 and simultaneously published in JAMA.

The trial enrolled 32 people at five medical centers in the U.S., United Kingdom and Australia, all of whom had lipoprotein(a) levels above 150 nmol/L, with a median level of 224 nmol/L. Eight participants received a placebo and the rest received one of four doses of SLN360 (30 mg, 100 mg, 300 mg and 600 mg) via a single subcutaneous injection. Participants were closely observed the first 24 hours after their injection and then assessed periodically for five months.

Overall findings showed that participants receiving 300 mg and 600 mg of SLN360 had a maximum of 96% and 98% reduction in lipoprotein(a) levels, respectively, and a reduction of 71% and 81% at five months compared to baseline. Those receiving a placebo saw no change in lipoprotein(a) levels. The highest doses also reduced LDL cholesterol by about 20%-25%. Researchers reported no serious safety concerns, and the most common side effect was 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, MACC, the study's lead author and an ACC past president. "These findings support further development of this therapy."

The study, which was extended, will continue to follow participants for a total of one year. In addition, the study sponsor is planning a separate phase 2 trial along with other studies to assess the safety and efficacy of a multi-dose regimen.

"Lipoprotein(a) is the last frontier in lipids," Nissen said. "There has never been a treatment that's been shown to benefit these patients. Now, multiple therapies are moving forward and showing very strong efficacy at reducing levels of lipoprotein(a). We hope they will also be shown to reduce the consequences of elevated lipoprotein(a) in ongoing studies."

In a related editorial comment, Brian A. Ference, MD, MPhil, MSc, adds, "Because of the uncertainty about the magnitude of [lipoprotein(a)] lowering needed to reduce the risk of cardiovascular events, it is important to continue to evaluate the safety and efficacy of the siRNA … A series of cardiovascular outcome trials evaluating multiple different antisense oligonucleotide and siRNA therapies will provide the most robust estimate of the clinical benefit of lowering [lipoprotein(a)] and help identify which individuals are likely to benefit most from lowering [lipoprotein(a)]."

Clinical Topics: Dyslipidemia, Advanced Lipid Testing, Lipid Metabolism

Keywords: ACC Annual Scientific Session, ACC22, Lipoprotein(a), RNA

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