Inclisiran

• inclisiran inhibits the synthesis of PCSK9 within hepatocytes, as opposed to the extracellular inhibition by the currently approved PCSK9 monoclonal antibodies
• inclisiran is a small interfering RNA (siRNA) that inhibits the hepatic translation proprotein convertase subtilisin-kexin type 9 (PCSK9), thereby upregulating the number of LDL-receptors on the hepatocytes
• PCSK9 directs LDL receptor (LDLR) for degradation by the lysosome
• due to less PCSK9 protein, more LDLR can be recycled to the hepatic membrane for LDL-C uptake
  
  
• in the ORION-9 trial, 482 heterozygous familial hypercholesterolaemia (FH) patients were randomized to either 300 mg inclisiran sodium or matching placebo administered at baseline, 3 months later and then every 6 months for a total of four doses and showed a mean placebo-adjusted LDL-C reduction of 47.9% at the primary efficacy timepoint (Day 510) and a time-averaged LDL-C reduction of 44.3% over the 18-month trial (1)
  • inclisiran has been shown to significantly lowered total cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, and triglycerides and was associated with an 18.6–25.6% reduction in lipoprotein(a) [LP(a)] levels (1,2)

Inclisiran had a favourable safety and tolerability profile

• adverse events at the injection site (such as redness, bruising, or swelling) were more common in the inclisiran group than in the placebo group, but most were mild and none were severe or persistent (1,2,3)

Reference:

• Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med2020;382:1520–1530
• Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ, Bisch JA, Richardson T, Jaros M, Wijngaard PLJ, Kastelein JJP.. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med 2020;382:1507–1519.
• Nishikido T, Ray KK.. Inclisiran for the treatment of dyslipidemia. Expert Opin Investig Drugs 2018;27:287–294.