Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol

In this Phase II study in patients with elevated LDL cholesterol at high risk of cardiovascular disease, inclisiran was associated with dose-dependent relative reductions in LDL cholesterol levels of 27.9-41.9% after single dose and 35.5-52.6% after two doses (P<0.001 v placebo).

Inclisiran is an investigational, chemically synthesized small interfering RNA molecule designed to target PCSK9 messenger RNA. The current study, ORION-1, was a dose-finding trial to evaluate the efficacy of different dosing regimens among patients with elevated LDL cholesterol levels despite receiving the maximum possible dose of a statin and who were considered to be at high risk for atherosclerotic cardiovascular disease.

 

The authors note that the greatest reduction (52.6%) in LDL cholesterol levels was observed in patients receiving the two-dose 300-mg regimen of inclisiran; this reduction is in a similar range to that achieved with monoclonal antibodies designed to target PCSK9.

 

Although symptoms of immune activation (often a concern with therapies targeting RNA) were rare, the authors note that infrequent side-effects cannot be ruled out due to its size and short duration (210 days of exposure). Patients in the trial will be offered the chance to enter a long-term extension and larger studies are warranted.