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

Abstract

Elevated lipoprotein(a) [Lp(a)] is a major independent risk factor for atherosclerotic cardiovascular disease (ASCVD), with limited response to traditional lipid-lowering therapies. Lepodisiran, a novel N-acetylgalactosamine-conjugated small interfering RNA, targets hepatic LPA message RNA to reduce apolipoprotein(a) production. Early-phase trials demonstrated > 90% sustained Lp(a) reduction with excellent safety and tolerability. The phase 2 ALPACA trial confirmed durable effects lasting up to one year after biannual dosing. Compared to other therapies, lepodisiran offers longer duration, high efficacy, and minimal side effects. Ongoing phase 3 studies aim to determine its impact on cardiovascular outcomes, potentially establishing a new standard in precise ASCVD risk management.

Key Words: Lepodisiran; Gene targeting; Atherosclerotic cardiovascular disease; Lipid lowering agents; Cardiovascular medicine

Core Tip: Lepodisiran is a novel N-acetylgalactosamine-conjugated small interfering RNA that durably reduces lipoprotein(a) [Lp(a)] levels by silencing hepatic LPA message RNA expression. It offers up to 94% sustained Lp(a) reduction with minimal side effects and extended dosing intervals (6-12 months). This therapeutic breakthrough addresses a key residual cardiovascular risk factor previously untreatable with conventional lipid-lowering agents.

INTRODUCTION

Cardiovascular disease (CVD) remains the foremost global health burden, accounting for an estimated 17.9 million deaths each year, representing approximately 32% of all global deaths, according to the World Health Organization[1]. In recent decades, research has shifted toward understanding residual cardiovascular risk beyond traditional lipid parameters. One such factor gaining considerable attention is lipoprotein(a) [Lp(a)], a genetically determined lipoprotein that confers both atherogenic and thrombogenic risk. Elevated Lp(a) has been strongly linked with premature atherosclerotic CVD (ASCVD), including coronary artery disease, ischemic stroke, and aortic valve stenosis[2,3].

Despite its clinical relevance, Lp(a) has long posed a therapeutic challenge. Traditional lipid-lowering therapies such as statins exert minimal impact, and in some cases paradoxically elevate Lp(a) levels[4]. Lepodisiran, a novel small interfering RNA (siRNA), offers a transformative approach by targeting the hepatic production of apolipoprotein (a)-a unique component of Lp(a). This review explores the structure and pathophysiological role of Lp(a), the limitations of current therapies, and how lepodisiran could revolutionize cardiovascular risk management. In view of the key role of Lp(a) in ASCVD, its structure, genetic mechanism, and clinical significance will be analyzed in detail in the following section.

LP(A) AND CARDIOVASCULAR RISK

Structure and biochemistry of Lp(a)

Lp(a) consists of a low-density lipoprotein (LDL)-like particle containing apolipoprotein B-100 attached via a disulfide bond to apolipoprotein(a) [apo(a)][5]. The apo(a) segment shares extensive homology with plasminogen, particularly in its kringle IV and V domains, contributing to its antifibrinolytic and pro-inflammatory properties[6]. The kringle IV type 2 (KIV-2) domain. A repeat region in apo(a) gene which exists in variable tandem repeats; plays a central role in determining plasma Lp(a) levels. Individuals with fewer KIV-2 repeats tend to produce smaller apo(a) isoforms that are more efficiently synthesized, resulting in higher Lp(a) concentrations[7].

Genetic regulation of Lp(a)

The LPA gene, located on chromosome 6q26-27, encodes for apo(a) and is the principal determinant of Lp(a) plasma levels[7,8]. Variations in KIV-2 repeat number explain up to 90% of inter-individual differences in Lp(a). Genome-wide association studies have validated LPA as a key locus influencing CVD risk[8,9].

Clinical significance

Multiple large-scale epidemiological studies have confirmed a causal relationship between elevated Lp(a) levels and ASCVD. In a pivotal meta-analysis by Lu et al[2], individuals in the top third of Lp(a) distribution had a 2.5-fold higher risk of coronary heart disease compared to those in the lowest third[2]. Further, elevated Lp(a) levels have been independently associated with aortic valve stenosis progression[10]. Current guidelines from the American College of Cardiology and American Heart Association now recognize Lp(a) as a “risk-enhancing” factor in ASCVD risk assessment[11].

THERAPEUTIC LIMITATIONS AND RATIONALE FOR SIRNA APPROACHES

Challenges with traditional lipid therapies

While statins remain foundational in lipid management, their effect on Lp(a) is negligible or even adverse. Several studies have shown that statin therapy can increase Lp(a) by up to 20%-25%[4]. PCSK9 inhibitors, such as evolocumab and alirocumab, have shown modest Lp(a) reductions of around 20%-30%, although their primary mechanism targets LDL cholesterol[12]. Niacin, once considered a potential therapy for Lp(a), showed reductions of 20%-30% but failed to demonstrate meaningful cardiovascular benefits in clinical outcomes and has since fallen out of favor due to poor tolerability[13]. Lipoprotein apheresis remains an option for individuals with extremely high Lp(a) levels and progressive CVD, but it is invasive, expensive, and limited in availability[14].

Emergence of RNA-based therapeutics

RNA interference offers a precision-based method to silence genes post-transcriptionally. siRNAs are short, double-stranded RNA molecules that, once inside hepatocytes, are incorporated into the RNA-induced silencing complex (RISC)[15]. The guide strand of the siRNA directs RISC to complementary sequences of message RNA (mRNA), leading to its cleavage and degradation. N-acetylgalactosamine (GalNAc)-conjugated siRNAs specifically bind to the asialoglycoprotein receptor, enabling targeted delivery to the liver where Lp(a) is synthesized[16].

Mechanism of action of lepodisiran

Lepodisiran is a GalNAc-conjugated siRNA that targets LPA mRNA in hepatocytes. Upon subcutaneous injection, the GalNAc moiety facilitates receptor-mediated endocytosis via the asialoglycoprotein receptor[16]. Inside the cell, lepodisiran becomes part of the RISC complex, which cleaves LPA mRNA, thereby halting production of apo(a) and reducing Lp(a) levels[17]. Preclinical models show high specificity and minimal off-target effects[18].

A key pharmacokinetic advantage of lepodisiran is its prolonged duration of action, attributed to the chemical stabilization of the siRNA strands and intracellular RISC residence. This allows for extended dosing intervals-potentially as infrequent as every 6 to 12 months-thus improving adherence[19]. Importantly, lepodisiran does not interfere with LDL receptor pathways, preserving compatibility with other lipid-lowering agents like statins and PCSK9 inhibitors[20].

Preclinical and phase 1 data

Preclinical studies in rodents and non-human primates demonstrated robust reductions in Lp(a) concentrations up to 90% with sustained effects for several months[18]. No significant hepatotoxicity, nephrotoxicity, or immune responses were noted. These findings set the stage for first-in-human clinical evaluation.

In the phase 1 trial led by Sahebkar et al[11], healthy volunteers with elevated Lp(a) received a single subcutaneous dose ranging from 100 mg to 400 mg. Lepodisiran produced dose-dependent reductions in plasma Lp(a), with the highest dose achieving a 94% decrease that persisted for over 180 days. Importantly, no serious adverse events or laboratory abnormalities were reported.

Phase 2 clinical data: The ALPACA trial

The ALPACA trial [apo(a) Lp(a) siRNA in patients with CVD] was a multicenter, randomized, double-blind, placebo-controlled phase 2 study enrolling 320 patients with established ASCVD and Lp(a) levels above 125 nmol/L[21]. Some of the key findings are given below: (1) A single 400 mg dose of lepodisiran reduced Lp(a) by 93.9% from day 60 through 180; (2) Two doses, administered six months apart, maintained Lp(a) reduction of 94.8% up to one year; (3) Lp(a) levels remained 74.2% below baseline even 360 days after the second dose; and (4) Adverse events were comparable between treatment and placebo arms, with no dose-limiting toxicities or discontinuations due to adverse effects[21]. These results underscore lepodisiran’s potential as a durable, safe, and effective agent for Lp(a) lowering.

COMPARATIVE OVERVIEW: LEPODISIRAN VS OTHER LP(A)-LOWERING THERAPIES

Olpasiran

Olpasiran, another GalNAc-siRNA developed by Amgen, targets the same LPA mRNA. The OCEAN(a)-DOSE trial demonstrated > 95% reductions in Lp(a), but its shorter duration necessitates more frequent dosing (monthly to quarterly)[22]. Long-term safety and major adverse cardiovascular events (MACE) outcome data remain pending.

Pelacarsen

Pelacarsen, an antisense oligonucleotide developed by Novartis/Ionis, achieves up to 80% Lp(a) reductions but requires monthly injections and has a higher incidence of injection site reactions[13]. It is currently being evaluated in the Lp(a) HORIZON outcome trial.

Lepodisiran advantages: (1) Longest duration of effect (6-12 months dosing); (2) Comparable or superior efficacy; and (3) High tolerability and minimal systemic side effects[17,21]. The comparison is given in Table 1.

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).

ONGOING AND FUTURE RESEARCH

A pivotal phase 3 cardiovascular outcome trial is underway to determine whether Lp(a) lowering with lepodisiran reduces MACE in high-risk populations[21]. Subgroup analyses are expected to clarify: (1) Genetic variability in Lp(a) response[8]; (2) Efficacy in diverse ethnic populations[20]; (3) Effects on aortic stenosis progression[10]; (4) Long-term hepatic and renal safety[19]; and (5) Combination strategies with statins or PCSK9 inhibitors[12,20].

CLINICAL IMPLICATIONS AND GUIDELINES

Currently, routine Lp(a) screening is recommended for individuals with premature ASCVD or a family history of early cardiovascular events[11]. However, no specific pharmacologic treatment targets Lp(a) in current guidelines due to a lack of conclusive outcome data. Lepodisiran’s durability, high efficacy [> 90% Lp(a) reduction], and favorable safety profile may eventually shift this paradigm. With accumulating evidence, especially if ongoing phase 3 trials confirm a reduction in MACE, guideline bodies may incorporate Lp(a) reduction as a formal therapeutic objective for high-risk populations[11,20]. If MACE benefit is validated, clinical guidelines could expand to recommend Lp(a) screening more broadly i.e., potentially for all patients with established ASCVD or those with Lp(a) ≥ 50 mg/dL, even in the absence of other lipid abnormalities. Moreover, treatment thresholds may be redefined, and Lp(a)-targeted therapies like lepodisiran may become part of standard lipid-lowering protocols in selected populations[20].

Despite promising early-phase data, several key questions remain regarding the clinical use of lepodisiran for Lp(a)-mediated ASCVD. Foremost among these is whether the substantial reduction in Lp(a) achieved with lepodisiran exceeding 90% in some trials will translate into meaningful reductions in cardiovascular events such as myocardial infarction, stroke, or cardiovascular death. While elevated Lp(a) is a well-established independent risk factor, definitive evidence of outcome benefit is awaited from ongoing phase 3 trials. Another unresolved issue concerns patient selection. It remains unclear whether lepodisiran should be used broadly in individuals with elevated Lp(a) for primary prevention or restricted to those with established ASCVD and markedly elevated levels. Additionally, long-term safety must be monitored closely, as the physiological roles of Lp(a), including wound healing and host defense, may be impacted by chronic suppression of apo(a) synthesis[15].

The optimal dosing strategy also warrants further evaluation. Although current trials support twice-yearly administration, it is uncertain whether dose adjustments based on body weight or Lp(a) levels will be required in clinical practice. Comparative effectiveness is another area of interest; lepodisiran must be evaluated against other emerging Lp(a)-lowering agents such as pelacarsen and olpasiran to determine superiority or potential combination benefits. Moreover, economic considerations will play a significant role in determining accessibility, as the cost-effectiveness of lepodisiran remains to be established, particularly for use in populations without established CVD. Lastly, there is an ongoing debate regarding whether Lp(a) should be routinely measured in all adults as part of cardiovascular risk stratification. If lepodisiran is approved, it may prompt guideline updates advocating universal or risk-based Lp(a) screening[16] as summarized in Table 2.

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.

If lepodisiran is proven effective in reducing MACE, its biannual dosing and high adherence potential could lead to substantial long-term economic benefits. These may include reduced medication costs, fewer healthcare visits, and lower rates of hospitalizations and interventions, ultimately making it a cost-effective strategy for ASCVD prevention in patients with elevated Lp(a)[17]. While lepodisiran shows promising efficacy, long-term safety data remain limited, warranting cautious optimism. Additionally, potential racial and ethnic disparities in Lp(a) levels and treatment response require further investigation.

CONCLUSION

Lepodisiran represents a milestone in cardiovascular therapeutics, uniquely addressing the unmet need of Lp(a) lowering. Its RNA-based mechanism offers durable suppression of apo(a) synthesis, translating to sustained reductions in plasma Lp(a). Clinical data to date affirm its safety and tolerability, and ongoing trials may cement its role in reducing cardiovascular events. However, key concerns remain: The phase 3 trials must validate its long-term impact on MACE, and the current evidence base is largely derived from Caucasian populations, highlighting the need for broader racial and ethnic representation. If these challenges are addressed, lepodisiran could reshape the landscape of personalized cardiovascular risk management.