Olpasiran is an investigational therapeutic agent under development to address a specific, genetically influenced risk factor associated with heart disease. This medication aims to provide a targeted approach for individuals with elevated levels of this inherited risk factor.
Olpasiran’s Mechanism of Action
Olpasiran functions as a small interfering RNA (siRNA), a type of medication that operates at a genetic level within the body. This drug utilizes a natural cellular process known as RNA interference, which can be thought of as a “dimmer switch” for specific gene expression. By harnessing this mechanism, olpasiran precisely targets the instructions for producing certain proteins.
Specifically, olpasiran is designed to enter liver cells, where it targets the messenger RNA (mRNA) produced by the LPA gene. This mRNA carries the genetic blueprint for creating apolipoprotein(a), a key protein component of lipoprotein(a). Once inside the liver cells, the siRNA in olpasiran binds to this specific mRNA, leading to its degradation.
Preventing the mRNA from being translated into apolipoprotein(a) effectively stops the liver from assembling new lipoprotein(a) particles. This action ensures that only the production of apolipoprotein(a) is inhibited, without affecting other vital cellular processes. The drug is delivered to the liver cells via a special chemical tag called N-acetylgalactosamine (GalNAc), ensuring targeted delivery.
Targeting Lipoprotein(a) for Cardiovascular Health
Lipoprotein(a), abbreviated as Lp(a), is a distinct type of fat-carrying particle in the blood that shares structural similarities with low-density lipoprotein (LDL). However, Lp(a) contains an additional protein, apolipoprotein(a), which distinguishes it. Elevated levels of Lp(a) are recognized as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD), including conditions like heart attacks and strokes.
This association is due to Lp(a)’s role in promoting inflammation, contributing to plaque buildup in arteries (atherogenesis), and increasing the tendency for blood clot formation (thrombosis). Unlike other cholesterol markers, Lp(a) levels are largely determined by an individual’s genetics, primarily influenced by variations in the LPA gene. Approximately 20% of the global population is estimated to have elevated Lp(a) levels.
The genetic basis of Lp(a) means that its levels are generally not significantly lowered by lifestyle changes, such as diet and exercise, or by commonly prescribed cholesterol-lowering medications like statins. This highlights the need for targeted treatments to reduce high Lp(a) concentrations in certain patient populations.
Clinical Trial Results
Olpasiran’s effectiveness in lowering Lp(a) has been demonstrated in clinical studies, particularly the Phase 2 OCEAN(a)-DOSE trial. This international, multicenter, randomized, double-blind, placebo-controlled study enrolled 281 patients with established atherosclerotic cardiovascular disease and elevated Lp(a) levels (greater than 150 nmol/L). Participants received various doses of olpasiran or a placebo.
The trial results showed substantial, dose-dependent reductions in Lp(a) concentrations. For instance, at week 36, patients receiving 75 mg of olpasiran every 12 weeks experienced a placebo-adjusted mean reduction in Lp(a) of 97.4%. Even higher doses, such as 225 mg administered every 12 weeks or every 24 weeks, led to reductions exceeding 100%. These significant reductions were largely maintained through week 48.
Beyond the initial treatment period, an extension phase of the OCEAN(a)-DOSE trial evaluated the duration of olpasiran’s effects after treatment discontinuation. For patients who had received higher doses, Lp(a) levels remained significantly reduced, with approximately 40% to 50% placebo-adjusted mean reduction observed nearly one year after the last injection. This demonstrates the long-acting nature of the therapy. The study also found that olpasiran led to a significant reduction in oxidized phospholipids (OxPL-apoB), a biomarker associated with atherosclerosis.
Administration and Safety Profile
Olpasiran is administered through subcutaneous injection, meaning it is given under the skin. In clinical trials, doses were typically administered every 12 weeks or every 24 weeks.
The overall safety and tolerability profile of olpasiran in clinical trials was generally favorable. The incidence of adverse events was similar between the olpasiran treatment groups and the placebo group. The most commonly reported adverse events were mild reactions at the injection site.
These injection-site reactions were typically mild and resolved on their own within 48 hours. Importantly, clinical trials did not show an increased incidence of muscle pain (myalgia), liver-related adverse events, or new-onset or worsening diabetes mellitus with olpasiran treatment.