OCEAN(a)-DOSE: Olpasiran Expresses Prolonged Reduction in Lp(a) Levels

Michelle L. O’Donoghue

Credit: Brigham and Women’s Hospital

Results from the OCEAN(a)-DOSE trial off-treatment extension period revealed the pharmacodynamic effects of olpasiran are reversible in patients with atherosclerotic cardiovascular disease (ASCVD) but persist for several months after treatment discontinuation.¹

These data showed individuals on olpasiran doses ≥75 mg experienced a 40–50% placebo-adjusted mean reduction in Lipoprotein(a) (Lp(a)) levels nearly 1 year after the final dose, without the identification of new safety signals.

“The current findings from the Phase 2 OCEAN(a)-DOSE program demonstrate that Lp(a) concentrations gradually return to baseline after discontinuation of treatment across all doses in a dose-dependent manner,” wrote the investigative team, led by Michelle L. O’Donoghue, MD, MPH, TIMI Study Group, Brigham and Women’s Hospital.

Olpasiran is a small interfering RNA (siRNA) molecule that blocks the expression of Lp(a) by preventing the translation of apolipoprotein(a) messenger RNA (mRNA). The Phase 2, dose-finding OCEAN(a) trial assigned 281 participants with ASCVD and Lp(a) >150 nmol/L to 1 of 4 active doses of olpasiran (10 mg, 75 mg, 225 mg Q12W, 225 mg Q24W) or placebo.²

Primary findings from OCEAN(a)-DOSE showed higher doses of subcutaneous olpasiran every 12 weeks led to >95% reductions in circulating Lp(a) at Week 36, with maintenance at Week 48 during the on-treatment phase. However, these data did not describe the rate of Lp(a) return to baseline and long-term safety after discontinuation of olpasiran during an extended off-treatment follow-up period.¹

After completion of the 48-week treatment phase, in-person study visits were conducted Q12W until blinded Lp(a) values returned to >80% of baseline or for ≥40 weeks after the last dose of the study drug. A protocol amendment in May 2022 defined the extension period as a minimum follow-up period of 24 weeks.

Among the total OCEAN(a)-DOSE population, 276 (98.2%) entered the off-treatment follow-up period. Median study exposure, calculated as treatment combined with the off-treatment phase, was reported as 86 weeks.

Upon analysis, for each of the Q12W dosing regimens, investigators found the effect of olpasiran on circulating Lp(a) levels was similar at the time of the last dose at 36 weeks and the end of treatment at 48 weeks (all P <.001).

In the off-treatment phase, the placebo-adjusted mean percent change in Lp(a) for the 10 mg Q12W olpasiran dose was –41.0%, –22.7%, –21.0% at 60, 72, and 84 weeks, respectively (all P <.001). For the 75 mg Q12W dose, the respective changes were –76.2%, –53.0%, and –44.0% (all P <.001).

Further, for the 225 mg Q12W dose, the respective off-treatment changes were –84.4%, –61.6%, –52.2%, and –36.4% (all P <.001). In the extension-follow-up period, the overall incidence of adverse events and serious adverse events were similar for participants treated with olpasiran and with placebo.

Injection site reactions (ISRs) were identified as adverse drug reactions with olpasiran, with the most common forms being mild to moderate localized pain, bruising, and erythema. A total of 3 participants discontinued olpasiran treatment due to ISRs, with the reactions described as mild to moderate.

O’Donoghue and colleagues indicated, overall, olpasiran appeared to be safe and well-tolerated, with durable pharmacodynamic effects among this population with ASCVD.

“The results of the ongoing Phase 3 trial will ultimately determine whether a strategy of Lp(a) lowering with olpasiran translates into a cardiovascular clinical benefit,” they added.

References

1. _{O’Donoghue, M, Rosenson, R, López, J. et al. The Off-Treatment Effects of Olpasiran on Lipoprotein(a) Lowering: OCEAN(a)-DOSE Extension Period Results. JACC. 2024 Aug, 84 (9) 790–797. https://doi.org/10.1016/j.jacc.2024.05.058}
2. _{O'Donoghue ML, Rosenson RS, Gencer B, et al. Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease. N Engl J Med. 2022;387(20):1855-1864. doi:10.1056/NEJMoa2211023}