Indications
Inclisiran is authorized in Europe for the treatment of primary hypercholesterolemia, both heterozygous familial and non-familial, as well as mixed dyslipidemia in adults. It is recommended as an adjunct to dietary interventions and can be used alongside a statin or in combination with other lipid-lowering therapies in patients who have not achieved their LDL-C targets despite the maximum tolerated statin dosage. Additionally, for individuals who are intolerant to statins or have contraindications, inclisiran can be administered as monotherapy or combined with other lipid-lowering treatments. In the United States, inclisiran is indicated as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, particularly for those needing further reduction in low-density lipoprotein cholesterol (LDL-C).
Pharmacodynamics
Inclisiran acts as a long-acting small interfering RNA (siRNA) aimed at reducing plasma levels of LDL-cholesterol (LDL-C). Clinical trials have demonstrated a significant reduction in LDL-C levels shortly after administration, with mean reductions ranging from 48-51% observed between 30 to 60 days post-dose. These reductions in LDL-C levels, persist at 53% even 180 days post-dose. In healthy volunteers, PCSK9 levels were decreased by 70-80%, resulting in LDL-C reductions between 27-60%. In patients with atherosclerotic cardiovascular disease, with or without diabetes, inclisiran has led to LDL-C level reductions of 28-52%. Although the long-term effects of inclisiran on cardiovascular outcomes remain to be fully explored, the reduction in LDL-C levels is associated with decreased cardiovascular risk.
Absorption
Inclisiran's prolonged duration of action is facilitated by its uptake into the liver. After subcutaneous administration in doses ranging from 24 mg to 756 mg, inclisiran showed a dose-proportional increase in systemic exposure. The observed mean peak concentration (Cmax) was 509 ng/mL, with a time to peak concentration (Tmax) of approximately 4 hours following administration of a 284 mg dose. The mean area under the curve (AUC0-inf) was recorded at 7980 ng·h/mL. Post 48 hours of dosing, inclisiran concentrations in plasma were undetectable. The pharmacokinetic characteristics of inclisiran following a single dose were consistent with those observed with multiple dosing.
Metabolism
Inclisiran undergoes metabolism through nucleases, which degrade it into smaller nucleotide fragments. It is not anticipated to be a substrate for cytochrome P450 enzymes, which indicates a metabolic pathway that is distinct from many other pharmacological agents.
Mechanism of Action
Inclisiran functions by targeting the molecular mechanisms responsible for the regulation of low-density lipoprotein cholesterol (LDL-C) levels in the bloodstream. It is chemically linked to triantennary N-acetylgalactosamine carbohydrates, which facilitate its binding to asialoglycoprotein receptors located on the surface of liver cells. This interaction promotes the efficient internalization of inclisiran into hepatocytes. Inside the cell, inclisiran associates with the RNA-induced silencing complex (RISC), which plays a critical role in RNA interference by identifying and degrading complementary messenger RNA (mRNA) strands. Through this association, inclisiran specifically binds to and cleaves mRNA encoding proprotein convertase subtilisin-kexin type 9 (PCSK9), thus inhibiting its translation and reducing PCSK9 production in the liver. Consequently, the reduction in PCSK9 levels allows for increased recycling of LDL receptors to the hepatocyte surface, enhancing the clearance of circulating LDL-C from the plasma.
