Subcutaneous administration of every 6 months was found to reduce low-density lipoprotein cholesterol (LDL-C) by 50% in patients with atherosclerotic cardiovascular disease (ASCVD) or an ASCVD risk-equivalent on a maximally tolerated statin regimen, according to study results published in the New England Journal of Medicine.
A small interfering RNA, inclisiran reduces the synthesis of proprotein convertase subtilisin-kexin type 9 in the liver.
In this study, 1561 patients with ASCVD and 1617 patients with an ASCVD risk equivalent were enrolled in 2 clinical trials (ORION-10 and ORION-11 trials, respectively; ClinicalTrials.gov identifiers: NCT03399370 and NCT03400800, respectively) were enrolled and followed for 18 months. Study participants were on maximally tolerated statin therapy to manage elevated LDL-C levels. In each study, patients were randomly assigned 1:1 to receive subcutaneous inclisiran 284 mg (n=781 in ORION-10 and n=810 in ORION-11) or placebo (n=780 in ORION-10 and n=807 in ORION-11). Injections were administered at baseline, 90 days, and every 6 months thereafter up to 540 days. Both studies co-primary outcomes were placebo-corrected LDL-C level percentage change from day 1 to day 510 and time-adjusted LDL-C level percentage change from baseline after day 90 to day 540.
The mean baseline LDL-C levels were 104.7±38.3 mg/dL (2.71±0.99 mmol/L) in ORION-10 and 105.5±39.1 mg/dL (2.73±1.01 mmol/L) in ORION-11. At 510 days, inclisiran treatment was associated with a reduction in LDL-C levels compared with placebo: ORION-10 trial: reduction, 52.3% (95% CI, -55.7 to -48.8; P <.001; time-adjusted reduction, 53.8%; 95% CI, -56.2 to -51.3; P <.001); ORION-11, reduction, 49.9% (95% CI, -53.1 to -46.6; P <.001; time-adjusted reduction, 49.2%; 95% CI, -51.6 to -46.8; P <.001).
Although adverse events occurred at comparable rates and were of similar nature in the 2 groups, a greater percentage of patients treated with inclisiran vs placebo reported injection site adverse events in the ORION-10 (2.6% vs 0.9%, respectively) and ORION-11 (4.7% vs 0.5%, respectively ) trials. Injection site reactions were mostly mild, without any persistent or severe complications.
“Our trials suggest that sustained reductions in LDL cholesterol levels are achievable with an
infrequent dosing schedule of inclisiran,” noted the authors.
Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020;382(16):1507-1519. doi:10.1056/nejmoa1912387