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

Abstract

Dyslipidemia is listed among important cardiovascular disease risk factors. Treating lipid disorders is difficult, and achieving desirable levels of LDL-cholesterol (LDL-C) is essential in both the secondary and primary prevention of cardiovascular disease. For many years, statins became the basis of lipid-lowering therapy. Nevertheless, these drugs are often insufficient due to their side effects and restrictive criteria for achieving the recommended LDL-C values. Even the addition of other drugs, i.e., ezetimibe, does not help one achieve the target LDL-C. The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) discovery has triggered intensive research on a new class of protein-based drugs. The protein PCSK9 is located mainly in hepatocytes and is involved in the metabolism of LDL-C. In the beginning, antibodies against the PCSK9 protein, such as evolocumab, were invented. The next step was inclisiran. Inclisiran is a small interfering RNA (siRNA) that inhibits the expression of PCSK9 by binding specifically to the mRNA precursor of PCSK9 protein and causing its degradation. It has been noticed in recent years that siRNA is a powerful tool for biomedical research and drug discovery. The purpose of this work is to summarize the molecular mechanisms, pharmacokinetics, pharmacodynamics of inclisiran and to review the latest research.

Inclisiran and lipoprotein apheresis in statin intolerance heterozygous FH patients: A case series

“…The safety, tolerability, and efficacy of inclisiran have been studied within the ORION clinical development program who demonstrated a sustained PCSK9 suppression of about 80% and time-adjusted LDL-C reduction of approximately 50% from baseline. Furthermore, the safety profile of inclisiran was found to be comparable to that of mAb PCSK9i and the most commonly reported adverse effect was a mild-to-moderate transient injection site reaction [3]. It provides a therapeutic opportunity to overcome drugs intolerance and decrease the burden of atherosclerotic cardiovascular disease.…”

“…Inclisiran is a novel small interfering RNA-based drug (siRNA) anti-PCSK9 play a role in patients when optimal LDL-C cannot be achieved by statins and/or mAb PCSK9i [3].…”

Therapeutic approach in the treatment of dyslipidemia: Novelties and challenges

“…Primenjuje se kao supkutana injekcija u dozi od 284 mg. Posle inicijalne primene leka, druga doza se dobija nakon tri meseca, a svaka sledeća na 6 meseci 29 . Glavna prednost inklisirana u odnosu na PCSK9 monoklonska antitela je režim doziranja i dugotrajniji efekat koji obezbeđuje bolju komplijansu 30 .…”

Treatment with Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors (PCSK9i): Current Evidence for Expanding the Paradigm?

“…44,45 Treatment with a PCSK9i is associated with reductions in triglycerides (TGs), VLDL cholesterol (VLDL-C) and VLDL remnants, intermediate-density lipoprotein cholesterol (IDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apoB and lipoprotein(a) (Lp[a]). 17,18,41,43,[46][47][48] Non-HDL-C (containing VLDL, IDL, LDL, chylomicron remnants, and Lp[a]) is advantageous over LDL-C since it is not influenced by TG variability and contains lipoprotein with remnant cholesterol. 35,41 The administration of PCSK9i also increases apolipoprotein A-I (apoA-I) and HDL-C. 41…”

“…35,53 Inclisiran reduces both the intracellular and extracellular levels of PCSK9, unlike mAbs which only influence the extracellular PCSK9 levels. 46 The clinical efficacy and safety of inclisiran in lowering LDL-C have been explored in randomized, placebo-controlled, double-blind clinical trials. 54,55 ORION-9, ORION-10, and ORION-11 phase 3 trials have demonstrated that the inclisiran regimen of 284 mg (equivalent to 300 mg inclisiran sodium) has good efficacy for LDL-C level reduction.…”