A new wave of RNA interference (RNAi) therapies is showing promise in significantly reducing lipoprotein(a) (Lp(a)) levels, a major risk factor for cardiovascular disease. Clinical trials of olpasiran and zerlasiran have demonstrated substantial reductions in Lp(a), offering potential new strategies for managing heart disease. These findings were presented at the American Heart Association's Scientific Sessions 2024 and published in JAMA Cardiology and the Journal of the American Medical Association.
Olpasiran: A Potent Lp(a) Reducer
Olpasiran, an RNA inhibitor, has demonstrated the ability to significantly lower Lp(a) levels in a Phase II clinical trial. The OCEAN(a)-DOSE trial, which included 282 patients with cardiovascular disease and elevated Lp(a) levels (above 150 nmol/L or 60 mg/dL), found that higher doses of olpasiran (75 mg or more every 12 weeks) reduced Lp(a) by more than 95% compared to placebo. The study, led by researchers at Mount Sinai, also indicated that Lp(a) levels continued to decline throughout the 36-week study period. According to Robert Rosenson, MD, professor of medicine (cardiology) at the Icahn School of Medicine at Mount Sinai, this is the first clinical trial to investigate the association between oxidized phospholipids on lipoprotein(a) and inflammatory mediators.
Zerlasiran: Gene Silencing for Lp(a) Reduction
Zerlasiran, a small interfering RNA (siRNA) therapeutic, also known as gene 'silencing' therapy, blocks the production of a protein needed to make Lp(a) in the liver. A Cleveland Clinic-led trial, the ALPACAR - Phase 2 Trial, found that zerlasiran reduced Lp(a) levels by more than 80% on average over 36 weeks, with minimal side effects. The 60-week phase 2 dose-finding trial enrolled 180 participants and studied three dosing strategies: 450 mg every 24 weeks for two doses, 300 mg every 16 weeks for three doses, and 300 mg every 24 weeks for two doses. Steven E. Nissen, M.D., Chief Academic Officer of the Heart, Vascular & Thoracic Institute at Cleveland Clinic, noted that Lp(a) substantially increases the risk of cardiovascular disease and aortic stenosis, and historically, this disorder has been untreatable because levels are primarily determined by the Lp(a) gene.
Clinical Implications and Future Directions
Elevated Lp(a) affects an estimated 64 million people in the United States and 1.4 billion people worldwide, with as many as 20%-25% of the world’s population having elevated levels. Unlike other types of cholesterol particles, Lp(a) levels are 80-90% genetically determined, making lifestyle changes ineffective. The structure of the Lp(a) particle causes the accumulation of plaques in arteries, which play a significant role in heart disease. While effective therapies exist to reduce the risk of heart disease by lowering LDL cholesterol and other lipids, currently there are no approved treatments to lower Lp(a).
Both olpasiran and zerlasiran have shown promising results in reducing Lp(a) levels, with adverse event rates comparable between the treatment and placebo groups. However, the ALPACAR trial enrolled primarily white, male participants, highlighting the need for further study in more diverse populations, as Lp(a) concentration is known to vary among different racial and ethnic groups. A Phase III outcomes trial is now underway to further evaluate olpasiran’s potential to improve clinical outcomes for cardiovascular patients. If successful, these innovative RNA-based approaches could offer a new and highly effective strategy for managing heart disease by targeting one of its most elusive risk factors.
