Persistent Lp(a) reduction after discontinuation of olpasiran in ASCVD patients with elevated Lp(a)

In the off-treatment period of the phase 2 OCEAN(a)-DOSE trial, the siRNA olpasiran continued to lower Lp(a) in a dose-dependent manner for more than a year compared with placebo, although Lp(a) levels gradually increased toward the baseline value.

This summary is based on the publication of O’Donoghue ML, Rosenson RS, López JAG, et al. - The Off-Treatment Effects of Olpasiran on Lipoprotein(a) Lowering: OCEAN(a)-DOSE Extension Period Results. J Am Coll Cardiol. 2024 Aug 27;84(9):790-797. doi: 10.1016/j.jacc.2024.05.058

Introduction and methods

Background

Lp(a) is an LDL-like particle in which apo(a) is covalently bound to apoB-100. This lipoprotein is thought to play a causal role in atherogenesis [1-5]. The siRNA molecule olpasiran inhibits Lp(a) production in hepatocytes by degrading the apo(a) mRNA. Previously, the OCEAN(a)-DOSE (Olpasiran Trials of Cardiovascular Events And LipoproteiN(a) Reduction-DOSE Finding Study) trial showed administration of olpasiran ≥75 mg every 12 weeks (up to week 36) reduced circulating Lp(a) levels at 36 and 48 weeks by >95% compared with placebo [6].

Aim of the study

The authors examined the rate of return of Lp(a) levels to baseline after discontinuation of olpasiran treatment during the OCEAN(a)-DOSE extended off-treatment period, as well as longer-term safety.

Methods

The OCEAN(a)-DOSE trial was an international, multicenter, double-blind, placebo-controlled, dose-finding, phase 2 RCT in which 281 patients with ASCVD and Lp(a) >150 nmol/L were randomized in a 1:1:1:1:1 ratio to subcutaneous olpasiran (10, 75, or 225 mg every 12 weeks (Q12W); or an exploratory dose of 225 mg every 24 weeks (Q24W)) or placebo. The study treatment period lasted 48 weeks, after which all participants were followed up during the extended off-treatment period for a minimum of 24 weeks. In the Q12W groups, olpasiran or placebo was administered at randomization and at 12, 24, and 36 weeks, whereas participants in the Q24W group received the study drug at randomization and 24 weeks.

The extended off-treatment period included 276 patients (98.2%). Median duration of study exposure (i.e., treatment plus off-treatment phases) was 86 weeks (Q1–Q3: 79–89). During the off-treatment phase, Lp(a) and fasting lipid levels, concomitant medications, and adverse events were assessed.

Main results

Lp(a) levels

• During the off-treatment phase, the placebo-adjusted mean percentage change from baseline in Lp(a) levels for olpasiran 75 mg Q12W was −76.2% (95%CI: −84.1% to −68.3%) at 60 weeks, −53.0% (95%CI: −61.7% to −44.3%) at 72 weeks, −44.0% (95%CI: −52.8% to −35.2%) at 84 weeks, and –27.9% at 96 weeks (all P<0.001).
• For patients treated with olpasiran 225 mg Q12W, the placebo-adjusted mean percentage changes from baseline in Lp(a) levels were −84.4% (95%CI: −92.3% to −76.4%), −61.6% (95%CI: −70.4% to −52.8%), −52.2% (95%CI: −61.1% to −43.3%), and –36.4% at 60, 72, 84, and 96 weeks, respectively (all P<0.001).
• Treatment with olpasiran 225 mg Q24W led to similar, albeit smaller, placebo-adjusted mean percentage Lp(a) reductions over time (all P≤0.001).

Safety

• The frequencies of treatment-emergent adverse events and serious adverse events during the off-treatment phase were similar for patients who had been treated with olpasiran and those who had received placebo.
• The incidence rates of adverse events of interest, such as myalgia, peripheral neuropathy, and liver-related and kidney-related adverse events, were also comparable between the treatment groups.

Conclusion

During the extended off-treatment period of the OCEAN(a)-DOSE trial, olpasiran continued to lower Lp(a) concentrations compared with placebo in ASCVD patients with elevated Lp(a) levels. Almost a year after the last dose was administered, participants who had received olpasiran 75 or 225 mg Q12W showed a placebo-adjusted mean Lp(a) reduction of 44%–52%. During the long-term follow-up, no new safety concerns were identified.

Combined with the results of the on-treatment phase, this trial suggests Lp(a) levels gradually return to baseline after discontinuation of olpasiran, across all doses and in a dose-dependent manner. The authors remark that “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.”

Find this article online at J Am Coll Cardiol.

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