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Olpasiran Trial of Cardiovascular Events and Lipoprotein(a) Reduction (OCEAN(a)) – Outcomes trial

Official Name: A Double-blind, Randomized, Placebo-controlled, Multicenter Study Assessing the Impact of Olpasiran on Major Cardiovascular Events in Participants With Atherosclerotic Cardiovascular Disease and Elevated Lipoprotein(a)

Inclusion Criteria:

Age 18 to ≤ 85 years
Lp(a) ≥ 200 nmol/L during screening
History of ASCVD as evidenced by history of either:
- Myocardial infarction and/or
- Coronary revascularization with percutaneous coronary intervention with stenting AND at least 1 additional risk factor (>65 yo, Residual CAD, Diabetes, h/o CVA or PAD)

Exclusion Criteria:

Severe renal dysfunction
Active liver disease, known hepatitis, or hepatic dysfunction
History of hemorrhagic stroke
History of major bleeding disorder
Planned cardiac surgery or arterial revascularization
Severe heart failure

Primary Outcome Measures :

Time to CHD death, myocardial infarction, or urgent coronary revascularization, whichever occurs first [ Time Frame: Anticipated median around 4 years

Olpasiran vs Placebo given by subcutaneous injection once every 12 weeks (Q12W).

Despite advances in preventing and managing cardiovascular (CV) disease, substantial residual risk remains. The identification of additional treatable risk factors is therefore critical to further reduce CV morbidity and mortality. Apolipoprotein(a) [apo(a)] was first identified from the low-density lipoprotein (LDL) fraction of human serum by geneticist Kare Berg in 1963.1 A little more than a decade later; he described the relationship between Lipoprotein(a) [Lp(a)] and the risk of coronary heart disease (CHD). (Lp(a)) consists of an apolipoprotein B (apoB)-containing-containing lipoprotein that is similar to LDL but bound to apo(a) via the apoB-100 protein. The plasma concentration of Lp(a) is primarily genetically determined (estimated at 70-≥90%),and its expression is controlled by the apo(a) gene (LPA). Numerous epidemiologic studies over the past 3 decades have reported an association between higher plasma Lp(a) concentrations and risk of atherosclerotic CV disease (ASCVD), particularly CHD. Moreover, an emerging number of genome-wide association and Mendelian randomization studies support a causal role for Lp(a) in atherogenesis and progression of calcific valvular aortic stenosis.

Although Lp(a) is a presumed causal risk factor for ASCVD,13 no pharmacological therapies are available that provide a large reduction of Lp(a) in plasma. Olpasiran is a small interfering (siRNA) molecule that interrupts the expression of the LPA gene by degrading the messenger RNA (mRNA) that encodes the apo(a) protein, thereby preventing its translation and subsequent assembly of the Lp(a) particle in the hepatocyte. Olpasiran is targeted to the liver via an N-acetylgalactosamine moiety that binds to the asialoglycoprotein receptor on the hepatic cell surface. Once inside the hepatocyte, the antisense strand of olpasiran is loaded into an RNA-induced silencing complex (RISC) while the sense strand is degraded. The loaded RISC then binds to apo(a) mRNA via the complementary antisense strand sequence of olpasiran and degrades it through RISC-associated argonaute proteins. Following its cleavage, the RISC complex dissociates and can target additional mRNA for silencing, thereby allowing for a prolonged duration of effect. Efficacy data collected from transgenic mice and cynomolgus monkeys suggest that a sustained reduction of >80% in plasma Lp(a) can be achieved with olpasiran. In phase 1 testing in adults with elevated Lp(a), a single dose of olpasiran reduced Lp(a) in a dose-dependent manner with doses of ≥9 mg reducing Lp(a) by >90% with a duration of effect that persisted for 3 to 6 months. To date, there are no identified safety concerns for olpasiran.

O’Donoghue, M.L.; Lopez, J.A.G.; Knusel, B.; Gencer, B.; Wang, H.; Wu, Y.; Kassahun, H.; Sabatine, M.S. Study Design and Rationale for the OCEAN(a)-DOSE (Olpasiran trials of Cardiovascular Events and LipoproteiN (a) reduction-DOSE Finding Study) Trial. Am. Heart J. 2022, 251, 61–69.

Cardiovascular Research with a patient oriented focus

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