RNA Inhibition of Lipoprotein(a) with Olpasiran: Effects on Oxidized Phospholipids and Primary Results of the OCEAN(a)-DOSE (TIMI 67) Off-Treatment Extension Period

Presented at the ESC Congress 2023 by: Michelle O’Donoghue, MD - Boston, MA, USA

Introduction and methods

Lipoprotein(a) (Lp(a)) is causally associated with different atherosclerotic diseases, such as MI/CAD, ischemic stroke, aortic stenosis, abdominal aortic aneurysm and peripheral arterial disease. Oxidized phospholipids (OxPL) are proinflammatory mediators that are believed to contribute to endothelial dysfunction and plaque destabilization. Lp(a) is the predominant carrier OxPL, thereby providing a possible mechanistic link by which Lp(a) is pro-atherogenic.

Olpasiran is a siRNA directed to hepatocytes. Olpasiran can bind apo(a) mRNA, thereby preventing protein translation of apo(a), which is an element of the Lp(a) molecule. Olpasiran can repeat it’s action, leading to a prolonged effect.

The phase 2 OCEAN(a)-DOSE study previously showed that doses ≥75mg every 12 weeks led to a >95% placebo-adjusted reduction in Lp(a) at 36 weeks. The goal of the current study was to investigate the effects of olpasiran on levels of oxidized phospholipids on apolipoprotein B-100 (oxPL-apoB). The effects of olpasiran on Lp(a) concentration after last dose and the extended safety profile after last olpasiran dose were examined as well.

In OCEAN(a)-DOSE, a total of 281 individuals with established ASCVD and Lp(a) >150 nmol/L were randomized to receive 10 mg SC Q12W, 75 mg SC Q12W, 225 mg SC Q12W, 225 mg SC Q24W, or Placebo SC Q12W. Patients in the Q12W groups received their last dose in week 36 and patients in the Q24W group received their last dose in week 24. OxPL-apoB was measured at baseline, at week 36 and at week 48. Patients entered an extended off-treatment period for a minimum of 72 weeks from randomization. Median follow-up time was 86 weeks.

Main results

• A dose-dependent effect in on-treatment % change in OxPL-apoB was observed. Patients receiving doses of ≥75 mg Q12W had a >90% reduction in OxPL-apoB in weeks 36 and weeks 48, compared to baseline.
• After last dose, reduced Lp(a)-levels remained sustained and only slowly increased. One year after the last administered dose, patients on doses ≥75 mg Q12W sustained a 40 to 50% placebo-adjusted reduction in Lp(a) levels.
• Treatment emergent adverse events remained balanced between treatment groups during the extended off-treatment safety period.

Conclusion

RNA inhibition of Lp(a) with olpasiran reduced pro-atherogenic levels of OxPL-apoB in addition to the reduction of Lp(a) that was presented earlier. After last dose, reduced Lp(a)-levels remained sustained and slowly increased over time. The ongoing phase 3 OCEAN(a)-Outcomes trial will further investigate the long-term clinical efficacy and safety of olpasiran.

- Our reporting is based on the information provided at the ESC Congress 2023 -