Inclisiran: A New Promising Agent in the Management of Hypercholesterolemia

Abstract

The discovery of proprotein convertase subtilisin-kexin type 9 (PCSK9), a serine protease which binds to the low-density lipoprotein (LDL) receptors and targets the receptors for lysosomal degradation, offered an additional route through which plasma LDL-cholesterol (LDL-C) levels can be controlled. Initially, the therapeutic approaches to reduce circulating levels of PCSK9 were focused on the use of monoclonal antibodies. To that effect, evolocumab and alirocumab, two human monoclonal antibodies directed against PCSK9, given on a background of statin therapy, have been shown to markedly decrease LDL-C levels and significantly reduce cardiovascular risk. The small interfering RNA (siRNA) molecules have been used recently to target the hepatic production of PCSK9. siRNA interferes with the expression of specific genes with complementary nucleotide sequences by affecting the degradation of mRNA post-transcription, thus preventing translation. Inclisiran is a long-acting, synthetic siRNA directed against PCSK9 and it has been shown to significantly decrease hepatic production of PCSK9 and cause a marked reduction in LDL-C levels. This review aims to present and discuss the current clinical and scientific evidence pertaining to inclisiran, which is a new promising agent in the management of hypercholesterolemia.

Patient adherence, compliance, and perspectives on evolocumab for the management of resistant hypercholesterolemia

“…Inclisiran is a long-acting small interfering RNA (siRNA) molecule directed against PCSK9, and it has been shown to significantly decrease hepatic production of PCSK9 and cause a marked reduction in LDL-C levels. 37 This agent is not licensed as yet and has not been proven to reduce cardiovascular outcomes, as of now. However, inclisiran appears very promising and, in the future, if approved, its use may lead to a significant improvement in adherence and compliance due to its very infrequent, 6-monthly dosing intervals.…”

Signaling pathways of nucleic acids for bone healing: A review

“…These drugs are lumasiran, vutrisiran, givosiran, and inclisiran, which are agents against primary hyperoxaluria type 1, transthyretin mediated amyloidosis, acute hepatic porphyria, and hypercholesterolemia, respectively. 1,[28][29][30][31] Like the mentioned siRNAs, there are a huge group of miRNAs and antagomirs that are already identified as remarkably stimulators of osteoblast/osteocytic lineage differentiation, proliferation, and survival. In Table 1, we show the most studied miRNAs and antagomirs in relation to bone signaling pathways, their targets, and their final response to bone turnover.…”

Progress and prospects of biological approaches targeting PCSK9 for cholesterol-lowering, from molecular mechanism to clinical efficacy

“…Inclisiran is composed of one 2′-deoxy, eleven 2′-fluoro-, and thirty-two 2′-O-methyl-modified nucleotides, and a triantennary N-acetylgalactosamine (GalNAc) that is conjugated to the 3′-end of the passenger strand. The asialoglycoprotein receptor recognizes the GALNAc inhibiting the uptake of Inclisiran, resulting in the reduction of PCSK9 mRNA by 70% [113]; (2) Antisense Oligonucleotides (ASOs) inhibit the PCSK9 mRNA protein synthesis decreasing intra and extracellular protein levels. SPC5001, the clinical grade product of this approach, is 14 base oligonucleotide relying on locked nucleic acid technology with higher binding and specificity for PCSK9 mRNA [12]; (3) it has been proposed to block the PCSK9 expression by targeting the ribosomal complex using biologically active small molecules, in this way PF-06446846 (PF846) a small active molecule has been developed that directly inhibits the translation of PCSK9 by stalling the 80S ribosome in codon 34.…”

“…In a follow-up, Orion-1 was a phase 2, double-blind, placebo-controlled, dose-finding study in 501 patients with a high risk of CVD with LDL-C levels > 70 mg/dL in the presence of atherosclerotic history or LDL-C > 100 mg/dL in the absence of risk of ASCVD history. The studies report on day 180 a significant reduction of LDL-C up to 50 mg/dL level that was obtained with two doses of 300 mg inclisiran at 48% of patients [113]. The ORION-7 study evaluated the effect of inclisiran on pharmacokinetics (PK) and pharmacodynamics (PD) in individuals with different degrees of renal impairment.…”