Lepodisiran, an siRNA targeting lipoprotein(a) for the potential future treatment of cardiovascular disease

KEYWORDS:

• ApoB
• LDL
• LDL-cholesterol
• lepodisiran
• Lp(a)
• Lp(a) inhibitor
• nucleic acid-based therapies
• siRNA

1. Introduction

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of global morbidity and mortality. As such, primary and secondary prevention strategies focus on mitigating ASCVD risk by lifestyle and pharmacological interventions. Lipoprotein(a) [Lp(a)] is an atherogenic apoB-containing lipoprotein, which is synthesized and assembled in the liver, the plasma levels of which are strongly associated with, and considered to be causative of, ASCVD [1]. Lp(a) is similar in size and composition to low-density lipoprotein (LDL), but in addition contains apo(a), a highly glycosylated protein of variable size, with structural homology to plasminogen, which is covalently bound to apoB-100. The size and plasma concentration of Lp(a) are genetically determined and controlled by the LPA gene [1]. Lp(a)’s contribution to ASCVD risk stems, in part, from its proatherogenic, prothrombotic, proinflammatory properties. The cargo of oxidized phospholipids associated with apo(a), in addition to the atherogenicity of the LDL-like particle, give Lp(a) enhanced athero-thrombogenicity when compared with an equimolar LDL particle [1].

In the follow-up of >400,000 participants in the UK Biobank, a linear relationship was observed between Lp(a) and ASCVD, with a hazard ratio of 1.11 (95% CI 1.10–1.12) for every 50 nmol/L (20 mg/dL) of Lp(a) rise [2]. Similarly, a Mendelian randomization study using three Copenhagen cohorts showed a 22% higher risk for myocardial infarction for a doubling of Lp(a) levels in patients with genetically determined elevated Lp(a), with a hazard ratio of 1.22 (95% CI, 1.09–1.37) [3]. Very high Lp(a) levels (>200 mg/dL, >500 nmol/L) are associated with a similar ASCVD risk to heterozygous familial hypercholesterolemia patients [4].

Most guidelines require measurement of Lp(a), a minimum of once during the adult lifetime to avoid underestimation of an individual’s global ASCVD risk. Whilst Lp(a) represents a continuous variable for ASCVD risk, the European Atherosclerosis Society (EAS) Guidelines propose a <30 mg/dL (<75 nmol/L) cutoff to ‘rule-out’ and a >50 mg/dL (>125 nmol/L) cutoff to ‘rule-in’ risk, above which includes 20% of the general population. Lp(a) singularly has limited discriminatory value in ASCVD risk algorithms; however, a significant and proportional baseline risk enhancement is seen with elevated Lp(a) levels [5].

Significant heterogeneity in apo(a) concentration is observed, with up to 90% genetically determined by the copy number variants (CNV) in the Kringle-IV type 2 domain (from 2 to >50 copies), and which demonstrates an inverse relationship with Lp(a) levels [5]. The LPA single nucleotide polymorphisms rs10455872 and rs3798220 have demonstrated the strongest association with ASCVD risk, as they are linked to short CNVs which produce smaller apo(a) isoforms, resulting in an elevated Lp(a) level [6]. Plasma Lp(a) levels are primarily dependent on the hepatic production rate, with the liver also implicated in Lp(a) particle uptake and clearance [7].

Lifestyle changes, such as exercise and diet modification, have minimal effect on circulating Lp(a) levels. However, patients with increased baseline ASCVD risk due to increased Lp(a) benefit from strict management of other modifiable cardiovascular risk factors such as LDL-cholesterol, blood pressure, glucose, and lifestyle changes. Although lipoprotein apheresis has a role in acute reduction in Lp(a), it is both expensive and time-consuming, which limits its availability [8]. Experimentally, both niacin and cholesteryl ester transfer protein inhibitors reduce Lp(a) levels up to 25%, but with nominal effect on cardiovascular risk. Monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9) (evolocumab and alirocumab) show similar reductions in Lp(a) with a 15% lowering of ASCVD risk [9], whereas statins fail to result in clinically significant changes in Lp(a) levels [10].

Recent therapies targeting Lp(a) at the level of mRNA transcription of apo(a) or binding of apo(a) to apoB-100 have demonstrated substantial reductions of Lp(a). Pelacarsen (Novartis; previously known as IONIS-APO(a)-LRx), an injectable therapy, is targeted to the liver by conjugation to N-acetylgalactosamine (GalNAc), uses antisense oligonucleotide (ASO) RNA technology, whereby a single short-strand DNA fragment binds to the target complementary apo(a) mRNA and thus mediates its degradation. A 35% (at 20 mg four weekly) to 80% (at 20 mg weekly) reduction was observed with pelacarsen, with 98% of the group on a monthly 80 mg dose achieving Lp(a) levels of <50 mg/dL (<125 nmol/L) [11]. Muvalaplin (Eli Lilly; previously known as LY3473329), the only available oral therapy, is a small-molecule inhibitor of Lp(a) production, which has a moderate Lp(a) reduction of up to 65% with daily doses of >100 mg [12].

Small interfering RNA (siRNA) therapies, which inhibit LPA transcription, include olpasiran (Amgen; previously known as AMG-890), zerlasiran (Silence Therapeutics; previously known as SLN360), and lepodisiran (Eli Lilly; previously known as LY3819469) (Table 1). The double-stranded RNAs are chemically modified for improved stability, with GalNac conjugation for hepatic targeted delivery. The olpasiran OCEAN(a)-DOSE trial reported up to a 100% reduction with 225 mg at 12- and 24-weekly dosing, with almost all participants achieving Lp(a) levels below the EAS recommended cutoff of 50 mg/dL (125 nmol/L) [13]. The single-dose study for zerlasiran yielded almost comparable results at 600 mg, lasting 150 days post administration [14].

Table 1. Comparison of siRNA-based Lp(a)-targeted therapies.

Drug	Optimal dose frequency	Lp(a) lowering efficacy	Current drug trial status	Reference
Olpasiran (AMG-890)	Once every 12 weeks	70% to 100%	Phase III	[13]
Zerlasiran (SLN360)	Not yet determined	46% to 98%	Phase II	[14]
Lepodisiran (LY3819469)	Once or twice yearly	41% to 97%	Phase II	[15]

Lepodisiran, a GalNAc-conjugated siRNA injectable agent being developed by Eli Lilly to silence LPA, decreases hepatic apo(a) production and reduces circulating Lp(a) levels. Nissen and colleagues, in a ‘first-in-human’ multicenter phase I randomized-controlled trial, involving 48 healthy adults (mean age 47 years; 65% male) without CVD and with above normal Lp(a) levels (≥75 nmol/L), with median Lp(a) of 113 nmol/L across all groups, assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses (4, 12, 32, 96, 304, and 608 mg) of subcutaneous lepodisiran out to a maximum of 48 weeks after administration [15].

Lepodisiran was well tolerated with no reported serious adverse drug-related effects. Injection site reactions were infrequent, low grade, transient, and similar across all lepodisiran doses and placebo groups. Transiently abnormal liver and muscle enzymes were also uncommon, observed in only two (4 mg and 96 mg doses) and three (4 mg (x2) and 608 mg doses) participants in the lepodisiran groups, respectively. No serological evidence for systemic hypersensitivity was observed.

Lepodisiran was detected in plasma as early as 1 h post-administration, reaching a peak by 10.5 h, and was undetectable (below the lower limit of quantitation) within 48 h, even at the highest doses, with dose-dependent plasma exposure, as assessed by area under the curve. Taken together, these pharmacokinetic findings were consistent with rapid hepatic uptake of lepodisiran.

Overall, the maximal median change from baseline in serum fasting Lp(a) concentrations was −41, −59, −76, −90, −96, and −97% in the 4, 12, 32, 96, 304, and 608 mg lepodisiran groups, respectively, compared with −5% in the placebo group. At the highest lepodisiran dose of 608 mg, Lp(a) declined rapidly, becoming undetectable between days 29 and 281, and remained ≥94% below baseline for 337 days (48 weeks). At lower lepodisiran doses, the reduced levels of Lp(a) were of lesser duration; however, those who received the 304 mg dose experienced a median Lp(a) reduction from baseline of 75% at 48 weeks.

2. Expert opinion

Epidemiologic, Mendelian randomization studies, and genome-wide association studies have established that Lp(a) is an independent and causative risk factor for ASCVD and calcific aortic valve disease. However, the pathophysiology and metabolism of Lp(a) are complex, and the link between Lp(a), its oxidized phospholipid cargo, and ASCVD remains to be fully elucidated. Nucleic acid-based therapies offer a promising approach to lowering elevated Lp(a) levels.

Lepodisiran is a GalNAc-conjugated siRNA targeting Lp(a) for the potential future treatment of ASCVD. Like several nucleic acid therapeutics currently under development, namely the ASO pelacarsen (given once monthly) and two other siRNAs, olpasiran (given every 12 weeks) and zerlasiran (optimal dose frequency yet to be determined), lepodisiran, by selectively inactivating LPA, prevents apo(a) synthesis, resulting in sustained lowering of circulating Lp(a). At present, no pharmacological therapies are approved by regulatory authorities.

Safety and tolerability studies reported to date are promising, with extended dose-dependent reductions in circulating Lp(a) of ≥90% at the higher lepodisiran doses. However, there are some important limitations to the ‘first-in-human’ phase I trial, including the small patient numbers, the moderate Lp(a) entry criteria, and the use of single, rather than multiple, lepodisiran dosing. Due to its extended duration, allowing once or twice-yearly dosing, lepodisiran may offer advantages over other injectable nucleic acid-based therapies.

The patients who will benefit the most from lepodisiran are yet to be defined. Though patients with low Lp(a) concentrations (e.g. from null variants) would not benefit nor be indicated for treatment, patients with variants associated with high levels of Lp(a) should respond well to this siRNA therapy. However, the cost effectiveness of the treatment with lepodisiran is yet to be revealed.

A phase I study (NCT05841277) evaluating the pharmacokinetics, safety, and efficacy of lepodisiran in an estimated 28 patients with normal and impaired renal function, followed up for up to 17 weeks, was due for completion in January 2024. The results from an ongoing phase II study (NCT05565742) evaluating the efficacy and safety of lepodisiran in an estimated 254 adults (age ≥40 years) with elevated Lp(a) (≥175 nmol/L) and at high ASCVD risk, followed up for 20 months, are due to be completed in October 2024, and the outcomes are awaited with interest.

Large-scale and long-term studies will be required to further evaluate the efficacy, safety, and durability of lepodisiran across multiple patient subgroups and regarding currently available lipid-lowering therapies. Whether sustained lowering of Lp(a) with lepodisiran translates into reduced risk of major adverse cardiovascular events will require large phase III studies and remains to be seen.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.