ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: N Engl J Med. 2020;382(16):1520–30. doi: 10.1056/NEJMoa1913805

Short summary: Inclisiran (a small interfering double-stranded RNA against PCSK9) is superior to placebo in reducing LDL-C among individuals with heterozygous Familial Hypercholesterolemia who are already on statins and ezetimibe.

Comment: Proprotein convertase subtilisin kexin type 9 (PCSK9) is synthesized primarily in the liver, and enters the circulatory system, where it binds to, and accelerates the degradation of hepatic LDL receptors. This process reduces the capacity of the liver to remove LDL-C from the circulation. Pharmacologic inhibition of PCSK9 by monoclonal antibodies against PCSK9 have been shown to reduce LDL cholesterol levels by more than 50%. However, monoclonal antibodies require administration every 2 to 4 weeks.

Inclisiran is a long-acting, small interfering double-stranded RNA agent, which reduces the production of PCSK9 in the liver. The current study examined the safety and efficacy of inclisiran in lowering LDL-C among individuals with heterozygous Familial Hypercholesterolemia.

Individuals with LDL cholesterol levels of at least 100 mg/dl (2.6 mmol/l), despite receiving a maximally accepted dose of statin therapy with or without ezetimibe, were randomized to receive either inclisiran 300 mg (n =242) or matching placebo (n =240). The study drug was administered as a subcutaneous injection on day 1, and then at 3, 9 and 15 months (The ORION-9 trial).

Two months after the last injection, LDL-C levels decreased by 39.7% from baseline in the inclisiran group and increased by 8.2% in the placebo group (between-group difference −47.9%). The LDL-C levels at 9 months decreased by 59.0 mg/dl in the inclisiran group and increased by 9.9 mg/dl in the placebo group (between-group difference −68.9 mg/dl). PCSK9 levels decreased by 60.7% in the inclisiran group and increased by 17.7% in the placebo group. Inclisiran was associated with lower levels of total cholesterol, non–HDL cholesterol, apolipoprotein B and triglycerides than the placebo, together with higher HDL cholesterol levels. Apart from higher rates of injection-site reaction in the inclisiran group (17.0% vs. 1.7%), the frequency of adverse events was similar in the two groups, as assessed according to system organ class.

The short-term findings of this study are very promising. We now need to wait for the results of cardiovascular disease outcome trials.