The Lp(a) Revolution: How New Therapies Could Rewrite Cardiovascular Risk
For decades, cholesterol has been the primary target in the fight against heart disease. But a growing body of evidence points to another, often overlooked, player: lipoprotein(a), or Lp(a). Genetic predisposition largely dictates Lp(a) levels, and shockingly, even individuals with optimal cholesterol profiles can face significantly elevated cardiovascular risk if their Lp(a) is high – defined as greater than 50 mg/dL. Now, a wave of innovative therapies is poised to change the landscape, potentially offering a new line of defense against the world’s leading cause of death.
Understanding the Lp(a) Threat
Lp(a) is a unique lipoprotein, essentially an LDL-like particle with a distinctive addition – apolipoprotein(a) (apo[a]). This unique structure contributes to its particularly potent atherogenic properties, meaning it actively promotes the buildup of plaque in arteries. Unlike LDL cholesterol, which responds to statins and PCSK9 inhibitors, Lp(a) remains stubbornly resistant to these conventional treatments, typically seeing only modest reductions of 20-30%. This resistance has fueled the search for therapies specifically designed to tackle this independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD), encompassing heart attacks, strokes, and peripheral artery disease.
The Pipeline: ASOs, siRNAs, and Small Molecule Inhibitors
The therapeutic approach to lowering Lp(a) is rapidly evolving, with several promising strategies in development. The frontrunners fall into two main categories: antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs). Both work by targeting the messenger RNA (mRNA) responsible for producing apo(a) in the liver, effectively reducing its synthesis. A third, distinct approach involves small molecule inhibitors.
ASOs: Pelacarsen Leads the Charge
Pelacarsen (AKCEA-APO[a]-LRx; Novartis and Ionis Pharmaceuticals) is the most advanced ASO in clinical trials. The pivotal phase 3 Lp(a)HORIZON trial (NCT04023552), enrolling over 8,300 patients with established ASCVD and Lp(a) levels ≥70 mg/dL, is evaluating its ability to reduce major adverse cardiovascular events (MACE). While initial completion was projected for 2025, it’s now expected in February 2026 to ensure sufficient event data. Phase 2 results demonstrated an impressive ~80% reduction in Lp(a) levels with a favorable safety profile, positioning it as a potential first-in-class therapy.
siRNAs: A Trio of Contenders
The siRNA space is equally exciting, with three key players: olpasiran (AMG890; Amgen), lepodisiran (LY3819469; Eli Lilly and Company), and zerlasiran (SLN-360; Silence Therapeutics). Olpasiran, in the phase 3 OCEAN(a) trial (NCT05581303), has already recruited over 7,200 patients with ASCVD and Lp(a) ≥200 nmol/L. Phase 2 data revealed a remarkable 94% Lp(a) reduction after 36 weeks of treatment. Lepodisiran, currently in the ACCLAIM-Lp(a) trial (NCT06292013), is taking a broader approach, enrolling 12,500 participants with both established ASCVD and high-risk primary prevention profiles, and has shown a 94% reduction in Lp(a) in Phase 2. Zerlasiran, while showing a 96.4% reduction in Lp(a) in its phase 2 ALPACAR-360 study, currently has its phase 3 program on hold.
Muvalaplin: The Oral Option
Beyond RNA-based therapies, muvalaplin (LY3819469; Eli Lilly and Company) offers a different mechanism. This small molecule inhibitor targets Lp(a) production directly, achieving a 63-65% reduction in Lp(a) in phase 1 trials, with 93% of participants reaching levels below 50 mg/dL. Importantly, it demonstrated a strong safety profile and, being an oral medication, could provide a more convenient option for patients. The ALPACA phase 2 trial is currently underway.
The Critical Question: How Much Lowering is Enough?
While these therapies demonstrate impressive Lp(a) reduction, the crucial question remains: how much lowering is clinically meaningful? The upcoming cardiovascular outcomes trials (CVOTs) – Lp(a)HORIZON, OCEAN(a), and ACCLAIM-Lp(a) – are designed to answer this. Researchers need to determine if lowering Lp(a) directly translates to fewer heart attacks and strokes, or if the observed benefits are simply correlated with other risk factors. Furthermore, understanding the optimal level of Lp(a) reduction and potential unintended consequences, such as impacts on wound healing or immune function, will be vital.
As Dr. Koschinsky emphasized, these trials are “critical for us to be able to address what we call in the field the Lp(a) hypothesis.” The results will not only validate the therapeutic potential of Lp(a) targeting but also fundamentally reshape our understanding of cardiovascular risk and prevention.
The future of cardiovascular care may well hinge on our ability to effectively manage Lp(a). These emerging therapies represent a significant step forward, offering hope for a new era of personalized medicine where a genetically determined risk factor can finally be addressed. What impact will these findings have on routine cardiovascular screening and treatment guidelines? Share your thoughts in the comments below!
