Baseline Lp(a) does not affect Lp(a) reduction achieved with olpasiran in ASCVD
In a prespecified analysis of OCEAN(a)-DOSE, olpasiran ≥75 mg reduced Lp(a) by >95% at 36 weeks compared with placebo in ASCVD patients with highly elevated Lp(a) levels, irrespective of baseline Lp(a) concentration.
This summary is based on the publication of Kaur G, Rosenson RS, Gencer B, et al. - Olpasiran lowering of lipoprotein(a) according to baseline levels: insights from the OCEAN(a)-DOSE study. Eur Heart J. 2024 Nov 20:ehae781 [Online ahead of print]. doi: 10.1093/eurheartj/ehae781
Introduction and methods
Background
Lp(a), an LDL-like particle in which apo(a) is covalently bound to apoB-100, is a presumed causal risk factor for atherosclerosis [1,2]. To date, there are no approved pharmacological therapies targeting Lp(a) available.
Olpasiran is an siRNA molecule that inhibits hepatic Lp(a) production 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 by >95% compared with placebo in patients with ASCVD [3]. However, it is not clear whether the efficacy of olpasiran depends on baseline Lp(a) levels.
Aim of the study
In a prespecified analysis of the OCEAN(a)-DOSE trial, the authors assessed the effect of olpasiran versus placebo on the change in Lp(a) levels in ASCVD patients stratified by baseline Lp(a) concentration.
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 was 48 weeks, after which all participants were followed up during the extended off-treatment period for a minimum of 24 weeks. At baseline, the median Lp(a) concentration was 260.3 nmol/L (IQR: 198.1–352.4; maximum: 714.8).
Outcomes
Outcomes were the percent and absolute changes in Lp(a) levels at 36 weeks as a function of baseline Lp(a) concentration. In addition, the proportions of patients achieving Lp(a) <75 nmol/L and <20 nmol/L were assessed.
Main results
Percent Lp(a) change
- At 36 weeks, the placebo-adjusted percent reduction in Lp(a) levels was >95% in patients treated with olpasiran ≥75 mg, regardless of baseline Lp(a) concentration.
- In the group randomized to olpasiran 75 mg Q12W, the placebo-adjusted percent Lp(a) reduction was 109.6% (95%CI: 100.9%–118.4%) in patients with baseline Lp(a) levels in the first quartile and 100.9% (95%CI: 90.9%–110.8%) in those with Lp(a) levels in the fourth quartile (P for interaction=0.32).
- For the 225 mg Q12W dose, the placebo-adjusted percent Lp(a) reduction ranged from 111.0% (101.3%–120.6%) in patients with baseline Lp(a) levels in the first quartile to 100.7% (95%CI: 91.4%–110.0%) in those with Lp(a) levels in the fourth quartile (P for interaction=0.29).
Absolute Lp(a) change
- For the 75 mg Q12W dose, the placebo-adjusted least-squares (LS) mean absolute Lp(a) reduction ranged from 190.8 nmol/L (150.4–231.3) in patients with baseline Lp(a) values in the first quartile to 475.0 nmol/L (429.1–520.9) in those with Lp(a) levels in the fourth quartile.
- For the 225 mg Q12W dose, the placebo-adjusted LS mean absolute Lp(a) reduction ranged from 189.7 nmol/L (145.3–234.2) in patients with baseline Lp(a) values in the first quartile to 434.1 nmol/L (391.3–477.0) in those with Lp(a) levels in the fourth quartile.
Proportion of patients achieving low Lp(a) levels
- In the group randomized to olpasiran 75 mg Q12W, 100% of the patients with baseline Lp(a) in the highest quartile (i.e., >352 nmol/L) achieved Lp(a) <75 nmol/L (i.e., a value below the “gray zone” of CVD risk estimation proposed by the European Atherosclerotic Society [4]). In addition, 80% of the patients reached Lp(a) <20 nmol/L (i.e., median value in Western general population [5]).
- In the group receiving the 225 mg Q12W dose, 100% of the patients with Lp(a) in the highest quartile achieved Lp(a) <75 nmol/L and 69% achieved Lp(a) <20 nmol/L.
Conclusion
In this prespecified analysis of the OCEAN(a)-DOSE trial, olpasiran ≥75 mg greatly reduced Lp(a) levels at 36 weeks compared with placebo in patients with ASCVD and Lp(a) >150 nmol/L, irrespective of baseline Lp(a) concentration. All patients receiving olpasiran ≥75 mg achieved Lp(a) <75 nmol/L, and the majority achieved Lp(a) <20 nmol/L. The authors do point out “it remains unknown how much of a reduction in Lp(a) may be required to reduce the risk of [MACE].”
References
- Emerging Risk Factors Collaboration; Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009;302:412–23. https://doi.org/10.1001/jama.2009.1063
- Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 2009;301:2331–9. https://doi.org/10.1001/jama.2009.801
- O’Donoghue ML, Rosenson RS, Gencer B, López JAG, Lepor NE, Baum SJ, et al. Small interfering RNA to reduce lipoprotein(a) in cardiovascular disease. N Engl J Med 2022; 387:1855–64. https://doi.org/10.1056/NEJMoa2211023
- Kronenberg F, Mora S, Stroes ESG, Ference BA, Arsenault BJ, Berglund L, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European atherosclerosis Society consensus statement. Eur Heart J 2022;43:3925–46. https://doi.org/10.1093/eurheartj/ehac361
- Patel AP, Wang (汪敏先) M, Pirruccello JP, Ellinor PT, Ng K, Kathiresan S, et al. Lp(a) (lipoprotein[a]) concentrations and incident atherosclerotic cardiovascular disease: new insights from a large national biobank. Arterioscler Thromb Vasc Biol 2021;41: 465–74. https://doi.org/10.1161/ATVBAHA.120.315291