Lp(a): a New Pathway to Target?

Abstract

Purpose of Review Over the past decades, genetic and observational evidence has positioned lipoprotein(a) as novel important and independent risk factor for cardiovascular disease (ASCVD) and aortic valve stenosis. Recent Findings As Lp(a) levels are determined genetically, lifestyle interventions have no effect on Lp(a)-mediated ASCVD risk. While traditional low-density lipoprotein cholesterol (LDL-C) can now be effectively lowered in the vast majority of patients, current lipid lowering therapies have no clinically relevant Lp(a) lowering effect. Summary There are multiple Lp(a)-directed therapies in clinical development targeting LPA mRNA that have shown to lower Lp(a) plasma levels for up to 90%: pelacarsen, olpasiran, and SLN360. Pelacarsen is currently investigated in a phase 3 cardiovascular outcome trial expected to finish in 2024, while olpasiran is about to proceed to phase 3 and SLN360’s phase 1 outcomes were recently published. If proven efficacious, Lp(a) will soon become the next pathway to target in ASCVD risk management.

Potential Novel RNA-Targeting Agents for Effective Lipoprotein(a) Lowering: A Systematic Assessment of the Evidence From Completed and Ongoing Developmental Clinical Trials

“…23 The results of this study are expected in 2023. 52 However, it is already known that Amgen, the manufacturer of olpasiran, plans to conduct a phase 3 trial (NCT05581303) shortly after the completion of the phase 2 study that will also test the effectiveness of olpasiran in patients at high cardiovascular risk. 44,49…”

“…SLN360 is another experimental antihyperlipidemic drug belonging to siRNA therapeutics with promising preliminary results regarding the reduction of serum Lp(a) levels. 52,53 As with olpasiran, double-stranded RNA SLN360 is conjugated to an N-acetylgalactosamine component that shows high affinity for endocytic asialoglycoprotein receptors, predominantly expressed on the surface of hepatocytes, which ensures selective uptake and concentrations of SLN360 in hepatocytes and the drug's hepatocyte-specific impact. 24,26,53 SLN360 has a similar mechanism of action to olpasiran (Fig.…”

Lipoprotein(a) and residual vascular risk in statin-treated patients with first acute ischemic stroke: A prospective cohort study

“…A study reported that reducing Lp (a) level by 63% with LA achieved a 94% reduction in the major adverse cardiovascular events over a mean treatment period of 4 years ( 53 ). RNA-targeted therapies such as pelacarsen, olpasiran, and SLN360 which are currently investigated in trials have shown to lower Lp(a) levels by 90% ( 54 ). Decrease of Lp(a) levels by 50 mg/dL in 5 years in individuals with preexisting CVD may reduce the recurrence risk of CVD by 20% ( 55 ).…”

Inclisiran—Safety and Effectiveness of Small Interfering RNA in Inhibition of PCSK-9

“…Recent studies and guidelines draw attention to lipoprotein (a) (Lp (a)) and its impact on the risk of ASCVD [ 105 , 109 , 110 ]. According to the 2019 guidelines, Lp(a) measurement should be considered in every adult at least once in a lifetime to identify individuals with congenital very high Lp(a) levels >180 mg/dL (>430 nmol/L) who are at a lifetime risk for ASCVD may be comparable to the risk associated with HeFH (recommendation class IIa) [ 1 ].…”