Lepodisiran: From genetic targeting to cardiovascular promise: A detailed narrative review of the literature

Table 1 Lepodisiran vs olpasiran vs pelacarsen

Feature	Lepodisiran	Olpasiran	Pelacarsen
Type	GalNAc-conjugated small interfering RNA (siRNA)	GalNAc-conjugated siRNA	Antisense oligonucleotide
Target	LPA mRNA (hepatocytes)	LPA mRNA (hepatocytes)	LPA mRNA (hepatocytes)
Mechanism	RNA interference degrades LPA mRNA	RNA interference inhibits apo(a) synthesis	RNase H-mediated degradation of LPA mRNA
Dosing frequency	Twice yearly (biannual)	Every 12-24 weeks depending on dose	Monthly subcutaneous injection
Route	Subcutaneous	Subcutaneous	Subcutaneous
Lp(a) reduction	> 90% reduction sustained for up to 48 weeks	Approximately 90%-95% reduction in phase 2 data	Approximately 80% reduction (dose-dependent)
Duration of action	Long (effects up to 1 year with single dose)	Moderate to long (dose-dependent)	Shorter; Requires regular monthly dosing
Phase of trials	Phase 2 completed; Phase 3 ongoing (ALPINE program)	Phase 2 completed; Phase 3 ongoing [OCEAN(a)-outcomes]	Phase 3 ongoing [Lp(a) HORIZON trial]
Safety profile	Well tolerated; Mild injection-site reactions	Well tolerated; Mild side effects noted	Generally safe; Injection-site reactions, minor flu-like symptoms
Notable advantage	Longest dosing interval	Rapid onset, high potency	Extensive phase 3 data under development

GalNAc: N-acetylgalactosamine; siRNA: Small interfering RNA; mRNA: Message RNA; Lp(a): Lipoprotein(a); apo(a): Apolipoprotein(a).

Table 2 Summary of lepodisiran and lipoprotein(a) in cardiovascular disease

Section	Key Information
Global CVD burden	Approximately 17.9 million deaths annually; 32% of global mortality[1]
Lp(a): Role and structure	LDL-like particle with apoB-100 + apo(a); Apo(a) homologous to plasminogen; Pro-atherogenic and pro-thrombotic[5,6]
Genetic basis	LPA gene on chromosome 6q26-27; KIV-2 copy number explains up to 90% of Lp(a) variability[7,8,9]
Clinical significance	Elevated Lp(a) linked with CHD, stroke, aortic stenosis; 2.5 × higher CHD risk in top Lp(a) tertile[2,3,10]
Guidelines	ACC/AHA recognizes Lp(a) as a risk-enhancing factor[11]
Limitations of existing therapies	Statins (increase) Lp(a) 20%-25%[4]; PCSK9 inhibitors (decrease); Lp(a) approximately 20%-30%[12]; Niacin poorly tolerated[13]; Apheresis effective but invasive and costly[14]
siRNA approach	GalNAc-siRNA targets liver via ASGPR; siRNA-RISC complex degrades LPA mRNA[15,16]
Lepodisiran: Mechanism	Subcutaneous GalNAc-siRNA that inhibits apo(a) synthesis; Long half-life allows 6-12 months dosing[16,17,19]
Preclinical data	Up to 90% Lp(a) reduction in animal models; No toxicity observed[18]
Phase 1 data	Single dose (100-400 mg), up to 94% Lp(a) (decrease) lasting > 180 days; No serious adverse events[17]
Phase 2 (ALPACA)	Single 400 mg dose: 93.9% (decrease) (day 60-180); Two doses: 94.8% (decrease) up to 1 year; 74.2% (decrease) even at day 360; Excellent safety profile[21]
Comparison with other therapies	Olpasiran: > 95% (decrease); Monthly dosing[22]; Pelacarsen: 80% (decrease); Monthly; More injection site reactions[13]; Lepodisiran: Comparable efficacy; Longest duration; Highly tolerable[17,21]
Ongoing research	Phase 3 MACE outcomes trial evaluating genetic/ethnic variability, safety, and combination therapies[8,10,19,20]
Clinical implications	Lp(a) testing in premature ASCVD or family history; Potential future inclusion of Lp(a)-lowering in guidelines[11,20]

CVD: Cardiovascular disease; apoB-100: Apolipoprotein B-100; GalNAc: N-acetylgalactosamine; siRNA: Small interfering RNA; mRNA: Message RNA; Lp(a): Lipoprotein(a); apo(a): Apolipoprotein(a); LDL: Low-density lipoprotein; KIV-2: Kringle IV type 2; CHD: Coronary heart disease; ACC/AHA: American College of Cardiology/American Heart Association; ASGPR: Asialoglycoprotein receptor; RISC: RNA-induced silencing complex; MACE: Major adverse cardiovascular events; ASCVD: Atherosclerotic cardiovascular disease.